Compound useful as reversible inhibitors of cysteine proteases

ABSTRACT

Disclosed are novel cathepsin S, K, F, L and B reversible inhibitory compounds of the formulas (I), (II), (Ia) and (Ib) further defined herein. The compounds are useful for treating autoimmune diseases. Also disclosed are processes for making such novel compounds.

RELATED APPLICATION DATA

This application claims benefit to U.S. Provisional Application serialNos. 60/153,738 filed Sep. 13, 1999 and 60/222,900 filed Aug. 3, 2000.

TECHNICAL FIELD OF THE INVENTION

This invention relates to peptidyl spiroheterocyclic, amidino andguanidino compounds. The compounds are reversible inhibitors of thecysteine protease cathepsin S, K, F, L and B and are therefore useful inthe treatment of autoimmune and other related diseases. The inventionalso relates to processes for preparing such compounds andpharmaceutical compositions comprising them.

BACKGROUND OF THE INVENTION

Cathepsin S and cathepsin K are members of the papain family, within thepapain superfamily of cysteine proteases. The papain family is thelargest group of cysteine proteases and includes proteases such ascathepsins B, H, K, L, O and S. (A. J. Barrett et al., 1996,Perspectives in Drug Discovery and Design, 6, 1). The cysteine proteaseshave important roles in human biology and diseases includingatherosclerosis, emphysema, osteoporosis, chronic inflammation andimmune disorders (H. A. Chapman et al., 1997, Ann. Rev. Physiol., 59,63). Cathepsin S plays a key role in regulating antigen presentation andimmunity (H. A. Chapman, 1998, Current Opinion in Immunology, 10, 93; R.J. Riese et al., 1998, J. Clin. Invest., 101, 2351; R. J. Riese et al.,1996, Immunity, 4, 357). Cathepsin S deficient mice have impairedinvariant chain degradation resulting in decreased antigen presentationand germinal center formation, and diminished susceptibility tocollagen-induced arthritis indicating the therapeutic potential for acathepsin S inhibitor (G. Shi et al., 1999, Immunity, 10, 197; T. Y.Nakagawa et al, 1999, Immunity, 10, 207)

The specificity of the immune response relies on processing of foreignprotein and presentation of antigenic peptide at the cell surface.Antigenic peptide is presented bound to MHC Class II, a heterodimericglycoprotein expressed in certain antigen presenting cells ofhematopoietic lineage, such as B cells, macrophages and dendritic cells.Presentation of antigen to effector cells, such as T-cells, is afundamental step in recognition of non-self and thus initiation of theimmune response.

Recently MHC Class II heterodimers were shown to associateintracellularly with a third molecule designated invariant chain.Invariant chain facilitates Class II transport to the endosomalcompartment and stabilizes the Class II protein prior to loading withantigen. Invariant chain interacts directly with Class II dimers in theantigen-binding groove and therefore must be proteolyzed and removed orantigen cannot be loaded or presented. Current research suggests thatinvariant chain is selectively proteolyzed by cathepsin S, which iscompartmentalized with MHC Class II complexes within the cell. CathepsinS degrades invariant chain to a small peptide, termed CLIP, whichoccupies the antigen-binding groove. CLIP is released from MHC Class IIby the interaction of MHC Class II with HLA-DM, a MHC-like molecule thusfreeing MHC Class II to associate with antigenic peptides. MHC ClassII-antigen complexes are then transported to the cell surface forpresentation to T-cells, and initiation of the immune response.

Cathepsin S, through proteolytic degradation of invariant chain to CLIP,provides a fundamental step in generation of an immune response. Itfollows that inhibition of antigen presentation via prevention ofinvariant chain degradation by cathepsin S could provide a mechanism forimmuno-regulation. Control of antigen-specific immune responses has longbeen desirable as a useful and safe therapy for autoimmune diseases.Such diseases include Crohn's disease and arthritis, as well as otherT-cell-mediated immune responses (C. Janeway and P. Travers, 1996,Immunobiology, The Immune System in Health and Disease, Chapter 12).Furthermore, cathepsin S, which has broad pH specificity, has beenimplicated in a variety of other diseases involving extracellularproteolysis, such as Alzheimer's disease (U. Muller-Ladner et al., 1996,Perspectives in Drug Discovery and Design, 6, 87) and atherosclerosis(G. K. Sukhova et al., 1998, J. Clin. Invest., 102, 576).

A cathepsin S inhibitor has been found to block the rise in IgE titersand eosinophil infiltration in the lung in a mouse model of pulmonaryhypersensitivity, suggesting that cathepsin S may be involved in asthma(R. J. Riese et al., J. Clin. Investigation, 1998, 101, 2351).

Another cysteine protease, cathepsin F has been found in macrophages andis also involved in antigen processing. It has been postulated thatcathepsin F in stimulated lung macrophages and possibly other antigenpresenting cells could play a role in airway inflammation (G.-P. Shi etal., J. Exp. Med., 2000, 191, 1177).

Cathepsin K, another cysteine protease has been found to be highlyexpressed in osteoclasts and to degrade bone collagen and other bonematrix proteins. Inhibitors of cathepsin K have been shown to inhibitbone resorption in mice. Therefore, cathepsin K may play a role inosteoclastic bone resorption and cathepsin K inhibitors may be useful inthe treatment of diseases involving bone resorption such as osteoporosis(F. Lazner et al., Human Molecular Genetics, 1999, 8, 1839).

Cysteine proteases are characterized by having a cysteine residue at theactive site which serves as a nucleophile. The active site also containsa histidine residue. The imidazole ring on the histidine serves as abase to generate a thiolate anion on the active site cysteine,increasing its nucleophilicity. When a substrate is recognized by theprotease, the amide bond to be cleaved is directed to the active site,where the thiolate attacks the carbonyl carbon forming an acyl-enzymeintermediate and cleaving the amide bond, liberating an amine.Subsequently, water cleaves the acyl-enzyme species regenerating theenzyme and liberating the other cleavage product of the substrate, acarboxylic acid.

Inhibitors of cysteine proteases contain a functionality that can reactreversibly or irreversibly with the active site cysteine. Examples ofreactive functionalities that have been described (D. Rasnick, 1996,Perspectives in Drug Discovery and Design, 6, 47) on cysteine proteaseinhibitors include peptidyl diazomethanes, epoxides, monofluoroalkanesand acyloxymethanes, which irreversibly alkylate the cysteine thiol.Other irreversible inhibitors include Michael acceptors such as peptidylvinyl esters and other carboxylic acid derivatives (S. Liu et al., J.Med Chem., 1992, 35, 1067) and vinyl sulfones (J. T. Palmer et al.,1995, J. Med Chem., 38, 3193).

Reactive functionalities that form reversible complexes with the activesite cysteine include peptidyl aldehydes (R. P. Hanzlik et al., 199 1,Biochim. Biophys. Acta., 1073, 33), which are non-selective, inhibitingboth cysteine and serine proteases as well as other nucleophiles.Peptidyl nitrites (R. P. Hanzlik et al., 1990, Biochim. Biophys. Acta.,1035, 62) are less reactive than aldehydes and therefore more selectivefor the more nucleophilic cysteine proteases. Various reactive ketoneshave also been reported to be reversible inhibitors of cysteineproteases (D. Rasnick, 1996, ibid). In addition to reacting with thenucleophilic cysteine of the active site, reactive ketones may reactwith water, forming a hemiketal which may act as a transition stateinhibitor.

Examples of cathepsin S inhibitors have been reported. J. L. Klaus etal. (WO 9640737) described reversible inhibitors of cysteine proteasesincluding cathepsin S, containing an ethylene diamine. In U.S. Pat. No.5,776,718 to Palmer et al. there is disclosed in it's broadest genericaspect a protease inhibitor comprising a targeting group linked througha two carbon atom chain to an electron withdrawing group (EWG). Thecompounds of the present application are structurally distinct and thusexcluded from the U.S. Pat. No. 5,776,718 patent with particularembodiments possessing unexpectedly greater activity than the closestcompounds of the prior art. Other examples of cathepsin S inhibitorshave been reported by E. T. Altmann et al, (WO 9924460, 1999) whichdescribes dipeptide nitrites asserted to have activity as inhibitors ofCathepsins B, K, L and S. The WO publication does not disclose anycompounds possessing an imino or guanidino moiety and fails to provideany description, methods or examples for particular spiroheterocyclicmoieities at the P2 position.

Additional peptidyl nitriles have been reported as protease inhibitors.For example, both nitriles and ketoheterocycles are described by B. A.Rowe et al. (U.S. Pat. No. 5,714,471) as protease inhibitors useful inthe treatment of neurodegenerative diseases. Peptidyl nitriles arereported by B. Malcolm et al. (WO 9222570) as inhibitors of picomavirusprotease. B. J. Gour-Salin (Can. J. Chem., 1991, 69, 1288) and T. C.Liang (Arch. Biochim. Biophys., 1987, 252, 626) described peptidylnitriles as inhibitors of papain

A reversible inhibitor presents a more attractive therapy thanirreversible inhibitors. Even compounds wit h high specificity for aparticular protease can bind non-target enzymes. An irreversiblecompound could therefore permanently inactivate a non-target enzyme,increasing the likelihood of toxicity. Furthermore, any toxic effectsresulting from inactivation of the target enzyme would be mitigated byreversible inhibitors, and could be easily remedied by modified or lowerdosing. Finally, covalent modification of an enzyme by an irreversibleinhibitor could potentially generate an antibody response by acting as ahapten.

In light of the above, there is a clear need for compounds whichreversibly and selectively inhibit cysteine proteases cathepsin S K, F,L and B for indications in which these proteases exacerbate disease.

BRIEF DESCRIPTION OF THE INVENTION

It is therefore an object of this invention to provide novel compoundsaccording to the formulas (I), (II), (Ia) and (Ib) as described hereinwhich reversibly inhibit the cysteine proteases cathepsin S, K, F, L andB. It is a further object of the invention to provide methods fortreating diseases and pathological conditions exacerbated by thesecysteine proteases such as, but not limited, to rheumatoid arthritis,multiple sclerosis, asthma and osteoporosis. It is yet a further objectof the invention to provide novel processes for preparation of theabove-mentioned novel compounds.

DETAILED DESCRIPTION OF THE INVENTION

A proposed mechanism of action of the cysteine protease inhibitors ofthis invention is that the inhibitors contain a functionality that canreact (reversibly or irreversibly) with the active site cysteine. Thereactive functionality is attached to a peptide or peptide mimic thatcan be recognized and accommodated by the region of the proteasesurrounding the active site. The nature of both the reactivefunctionality and the remaining portion of the inhibitor determine thedegree of selectivity and potency toward a particular protease.

Given the similarity of the active sites in cysteine proteases, it maybe anticipated that a given class of inhibitors might have activityagainst more that one cysteine protease. It may also be expected thatdue to structural differences between individual cysteine proteases,different compounds of the invention may have different inhibitorypotencies against different cysteine proteases. Thus some of thecompounds of the invention may also be expected to be most effective intreating diseases mediated by cysteine proteases that they inhibit mostpotently. The activity of particular compounds disclosed herein againstcysteine proteases cathepsin S, K, F, L and B may be determined by thescreens described in the section entitled “Assessment of BiologicalProperties.”

In one broad generic aspect, the invention provides novel compounds ofthe formula (I):

wherein:

Het is piperidinyl, pyrrolidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl,hexahydropyridazinyl, piperazinyl,1,4,5,6-tetrahydropyrimidin-2-ylamine, dihydro-oxazolyl,1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide,isothiazolidinyl-1,1-dioxide or imidazolidinyl-2,4-dione, each beingoptionally substituted with one or more R₅;

Y is O or S;

R₁ is C1-5 alkyl, C1-5 alkoxy, aryloxy, C3-7 cycloalkyl, phenyl, benzyl,naphthyl, tetrahydronaphthyl, C1‥5alkylsulfonylC1-5alkyl,C3-7cycloalkylsulfonylC1-5alkyl, arylsulfonylC1-5alkyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl, benzoxazolyl, quinoxalinyl, or amino;wherein R₁ is optionally substituted by one or more R_(a);

R_(a) is C1-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-5 alkoxy, C1-5alkanoyl, C1-5alkanoyloxy, aryloxy, benzyloxy, C1-5alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-8 alkyl,aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(a) is C1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byalkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, C1-5alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy,arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, halogen, hydroxy, oxo,carboxy, cyano, nitro, amidino or guanidino, R_(a) may be furtheroptionally substituted by one or more R_(b);

R_(b) is C1-5 alkyl, C3-6 cycloalkyl, aryl, C1-5 alkoxy, aryloxy,benzyloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino orguanidino;

R₂ is hydrogen or C1-3 alkyl;

R₃ is hydrogen, C1-5 alkyl, C2-5alkylene, C3-7 cycloalkyl, arylC1-3alkylor aryl wherein R₃ is optionally substituted by one or more R_(c);

R_(c) is C1-5 alkyl, C3-7 cycloalkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, C1-5 alkoxy, aryloxy, C1-5 alkanoyl, aroyl,C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-5 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(c) is C ₁₋₅ alkanoylamino, aroylamino, C1-5 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-5alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, C1-5alkoxycarbonylamino, aryloxycarbonylamino, C1-5 alkylcarbamoyloxy,arylcarbamoyloxy, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-5 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, halogen, hydroxy, oxo,carboxy, cyano, nitro, amidino or guanidino, R_(c) may be furtheroptionally substituted by one or more R_(d);

R_(d) is C1-5 alkyl, C3-6 cycloalkyl, aryl, arylalkyl, C1-5 alkoxy,aryloxy, arylC1-5alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy,cyano, nitro, amidino or guanidino;

R₄ is hydrogen or C1-3 alkyl;

R₅ is C1-5 alkyl chain optionally interrupted by one or two O or S,phenyl, naphthyl, arylC1-3alkyl, furanyl, thienyl, pyrrolyl, imidazolyl,pyridinyl, pyrimidinyl, C1-5 alkanoyl, aroyl, C1-5 alkoxycarbonyl,aryloxycarbonyl, benzyloxycarbonyl, carbamoyl wherein the nitrogen atommay be independently mono or disubstituted by C1-5 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienyl,pyrrolyl, thiazolyl, imidazolyl, pyridinyl, benzimidazolyl orquinolinyl,

or R₅ is C1-5 alkanoylamino, aroylamino, C1-5 alkylthio wherein thesulfur atom may be oxidised to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidised to a sulfoxide or sulfone, C1-5alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or disubstituted by alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyridinylcarbonyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl or arylsulfonyl, or R₅ ishalogen, hydroxy, oxo, carboxy, cyano, nitro, amidino or guanidino, R₅may be further optionally substituted by one or more R_(e);

R_(e) is C1-5 alkyl, C3-6 cycloalkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl,thiopyranyl, furanyl, thienyl pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,benzoxazolyl, quinoxalinyl, C1-5 alkoxy, aryloxy, aroyl, amino whereinthe nitrogen atom may be independently mono or di-substituted by C1-5alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, furanyl, thienyl,pyrrolyl or pyridinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro,benzyloxy, arylC1-3alkoxycarbonyl, amidino or guanidino;

X is O or S and

pharmaceutically acceptable derivatives thereof.

In another embodiment of the invention, there are provided novelcompounds of the formula (I) as described immediately above, andwherein:

Het is piperidinyl, pyrrolidinyl, tetrahydropyranyl ortetrahydrothiopyranyl each ring being substituted with one or more R₅;

Y is O;

R₁ is C1-3 alkyl, C1-3alkoxy, C3-7 cycloalkyl, phenyl, benzyl, naphthyl,tetrahydronaphthyl, piperidinyl, morpholinyl, piperazinyl, furanyl,thienyl, pyridinyl, isoxazolyl, pyrazinyl, indolyl, quinolinyl,benzofuranyl, benzimidazolyl, benzoisoxazolyl or amino; wherein R₁ isoptionally substituted by one or more R_(a);

R_(a) is C1-3 alkyl, phenyl, naphthyl, piperidinyl, indolinyl,morpholinyl, piperazinyl, furanyl, thienyl, benzimidazolyl, C1-3 alkoxy,C1-3 alkanoyl, phenoxy, naphthyloxy, benzyloxy, C1-3 alkoxycarbonyl,benzoyloxy, carbamoyl wherein the nitrogen atom may be independentlymono or di-substituted by C1-5 alkyl, phenyl, piperidinyl, morpholinyl,piperazinyl, furanyl, thienyl or pyridinyl, or R_(a) is C1-5alkanoylamino, benzoylamino, C1-3 alkylsulfonyl, phenylsulfonyl, ureidowherein either nitrogen atom may be independently substituted by alkyl,phenyl, piperidinyl, morpholinyl, furanyl, thienyl or pyridinyl, C1-3alkoxycarbonylamino, C1-5 alkylcarbamoyloxy, C1-5 alkylsulfonylamino,phenylsulfonylamino, C1-5 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, phenyl, piperidinyl, morpholinyl, piperazinyl, furanyl,thienyl or pyridinyl, halogen, hydroxy, oxo, carboxy, nitro or cyano,R_(a) may be further optionally substituted by one or more R_(b);

R_(b) is halogen, hydroxy, benzyloxy, oxo or cyano;

R₂ is hydrogen;

R₃ is C1-5 alkyl or C2-5 alkylene, C4-6 cycloalkyl or benzyl wherein R₃is optionally substituted by one or more R_(c);

R_(c) is C1-4 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, C1-4 alkoxy,phenoxy, benzoyl, benzyloxy, indolinyl, imidazolyl, C1-3alkylthio,C1-3alkylsulfonyl, halogen, hydroxy, oxo, carboxy, nitro or cyano, R_(c)may be further optionally substituted by one or more R_(d);

R_(d) is methyl, phenyl, benzyl, benzyloxy, C1-3alkoxy, halogen,hydroxy, nitro or cyano;

R₄ is hydrogen;

R₅ is C1-4alkyl chain optionally interrupted by one O or S atom, phenyl,phenylC-2alkyl, furanyl, pyrimidinyl, thienyl, C1-3 alkanoyl, benzoyl,C1-4 alkoxycarbonyl, carbamoyl wherein the nitrogen atom may beindependently mono or disubstituted by C1-5 alkyl, phenyl, piperidinyl,morpholinyl, piperazinyl, furanyl, thienyl or pyridinyl, C1-3 alkylthio,phenylthio, C1-5 alkylaminosulfonyl, phenylaminosulfonyl, C1-5alkylaminowherein the nitrogen atom may be independently mono- or disubstituted bynaphthylsulfonyl or pyridinylcarbonyl, halogen, hydroxy, carboxy, oxo orcyano, R₅ may be further optionally substituted by one or more R_(e);

R_(e) is C1-3 alkyl, C5-6 cycloalkyl, phenyl, naphthylmethyl,piperidinyl, morpholinyl, piperazinyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, benzimidazolyl, quinolinyl, isoquinolinyl, C1-4alkoxy, benzoyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-5 alkyl, phenyl, piperidinyl, morpholinyl,furanyl, thienyl or pyridinyl, halogen, hydroxy, oxo or cyano; and

X is O.

In yet another embodiment of the invention, there are provided novelcompounds of the formula (I) as described immediately above, andwherein:

R₁ is methyl, ethyl, phenyl, piperidinyl, morpholinyl, piperazinyl,pyridinyl, pyrazinyl, turanyl, thienyl, benzyl, benzofuranyl,cyclohexyl, quinolinyl or amino; wherein R₁ is optionally substituted byone or more R_(a);

R_(a) is C1-3 alkyl, phenyl, piperidinyl, thienyl, C1-3 alkoxy, phenoxy,C1-3 alkanoyl, C1-3 alkoxycarbonyl, benzyloxy, C1-3 alkanoylamino,thiophenyl, benzimidazolyl, C1-3 alkylthio or chloro, R_(a) may befurther optionally substituted by one or more R_(b);

R_(b) is bromo, chloro, fluoro, iodo, hydroxy, oxo or cyano;

R₃ is methyl, ethyl, n-propyl, n-butyl, isobutyl, propene, butene,isobutene, C3-7 cycloalkyl or benzyl wherein R3 is optionallysubstituted by one or more R_(c);

R_(c) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, methoxy, ethoxy, methylthio, ethylthio, cyclohexyl, phenyl,naphthyl, imidazolyl, indolinyl, cyclohexyl, bromo, chloro, fluoro,iodo, hydroxy, oxo, carboxy, nitro, benzoyl, benzyloxy,N-benzylimidazolyl or cyano, R_(c) may be further optionally substitutedby one or more R_(d);

R_(d) is methyl, methoxy, ethoxy, chloro, fluoro, nitro or hydroxy;

R₅ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,phenyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, isobutyloxycarbonyl,tert-butoxycarbonyl and pyrimidinyl, R₅ may be further optionallysubstituted by one or more R_(e);

R_(e) is methyl, ethyl, n-propyl, isopropyl, phenyl, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxycarbonyl, bromo,chloro, fluoro, iodo, hydroxy, oxo or cyano.

In yet still another embodiment of the invention, there are providednovel compounds of the formula (I) as described immediately above, andwherein:

Het is piperidinyl or pyrrolidinyl;

R₁ is N-acetylaminophenyl, chlorophenyl , methoxyphenyl,m-phenoxyphenyl, morpholinyl, pyrazinyl, pyridinyl, furanyl,chlorothienyl, thienyl or thienylmethyl;

R₃ is n-butyl, isobutyl, 2,2-dimethylpropyl, cyclohexylmethyl,p-methoxybenzyl or 2-naphthylmethyl; and

wherein the configuration at the stereocenter defined by R₂ and R₃ whenthey are different and the carbon they are attached to is defined as L;and

R₅ is methyl, propyl, isopropyl, ethoxycarbonyl, benzyloxycarbonyl,benzyl, phenethyl, N,N-dimethylaminoacetyl or pyrimidinyl.

In yet a further embodiment of the invention, there are provided novelcompounds of the formula (I) as described immediately above, andwherein:

Het is piperidin-4-yl or pyrrolidinyl;

R₁ is morpholinyl or N-acetylaminophenyl;

R₃ is 2,2-dimethylpropyl or cyclohexylmethyl; and

R₅ is methyl, propyl, isopropyl, ethoxycarbonyl, benzyloxycarbonyl,benzyl, phenethyl, N,N-dimethylaminoacetyl or pyrimidinyl.

In a second broad generic aspect of the invention, there are providednovel compounds of the formula (II):

wherein:

Het is azepanyl, piperidinyl, pyrrolidinyl, azetidinyl, oxepanyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, oxetanyl,azocanyl, oxocanyl, 1,3-diazocanyl, 1,4-diazocanyl, 1,5-diazocanyl,1,3-dioxocanyl, 1,4-dioxocanyl, 1,5-dioxocanyl, 1,3-oxazocanyl,1,4-oxazocanyl, 1,5-oxazocanyl, 1,3-diazepanyl, 1,4-diazepanyl,1,3-dioxepanyl, 1,4-dioxepanyl, 1,3-oxazepanyl, 1,4-oxazepanyl,1,2-thiazocanyl-1,1-dioxide, 1,2,8-thiadiazocanyl-1,1-dioxide,1,2-thiazepanyl-1,1-dioxide, 1,2,7-thiadiazepanyl-1,1-dioxide,tetrahydrothiophenyl, hexahydropyrimidinyl, hexahydropyridazinyl,piperazinyl, 1,4,5,6-tetrahydropyrimidinyl, pyrazolidinyl,dihydrooxazolyl, dihydrothiazolyl, dihydroimidazolyl, isoxazolinyl,oxazolidinyl, 1,2-thiazinanyl- 1,1-dioxide,1,2,6-thiadiazinanyl-1,1-dioxide, isothiazolidinyl-1,1-dioxide,imidazolidinyl-2,4-dione, imidazolidinyl, morpholinyl, dioxanyl,tetrahydropyridinyl, thiomorpholinyl, thiazolidinyl, dihydropyranyl,dithianyl, decahydro-quinolinyl, decahydro-isoquinolinyl,1,2,3,4-tetrahydro-quinolinyl, indolinyl, octahydro-quinolizinyl,dihydro-indolizinyl, octahydro-indolizinyl, octahydro-indolyl,decahydroquinazolinyl, decahydroquinoxalinyl,1,2,3,4-tetrahydroquinazolinyl or 1,2,3,4-tetrahydroquinoxalinyl;

A C6-C10 bridged bicyclo wherein one or more carbon atoms are optionallyreplaced by a heteroatom chosen from N, O and S;

each being optionally substituted with one or more R₅;

Y is C(O), C(S) or S(O)₂;

R₁ is a bond, hydrogen, C1-10 alkyl, C1-10 alkoxy, aryloxy, C3-8cycloalkyl, C3-8 cycloalkyloxy, aryl, benzyl, tetrahydronaphthyl,indenyl, indanyl, C1-10alkylsulfonylC1-10alkyl,C3-8cycloalkylsulfonylC1-10alkyl, arylsulfonylC1-10alkyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, tetrahydropyranyl,tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl, pyrazolyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,benzisoxazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl,benzoxazolyl and quinoxalinyl, heterocyclyloxy wherein the heterocyclylmoiety is selected from those herein described in this paragraph,hydroxy or amino; wherein R₁ is optionally substituted by one or moreR_(a);

R_(a) is a bond, C1-10 alkyl, C3-8 cycloalkyl, aryl, tetrahydronaphthyl,indenyl, indanyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, C1-10 alkoxy, C1-10alkanoyl,C1-10alkanoyloxy, aryloxy, benzyloxy, C1-10 alkoxycarbonyl,aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

or R_(a) is C1-10 alkanoylamino, aroylamino, C-10 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(a) is C1-10 alkoxycarbonylamino, aryloxycarbonylamino, C1-10alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further optionally substituted by oneor more R_(b);

with the proviso that R₁ and R_(a) simultaneously cannot be a bond;

R_(b) is a C1-6 saturated or unsaturated branched or unbranched carbonchain optionally partially or fully halogenated wherein one or morecarbon atoms are optionally replaced by O, N, S(O), S(O)₂ or S andwherein said chain is optionally independently substituted with 1-2 oxogroups, —NH₂, or one or more C1-4 alkyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl;

or R_(b) is C3-6 cycloalkyl, aryl, aryloxy, benzyloxy, halogen, hydroxy,oxo, carboxy, cyano, nitro, mono-C1-5alkylamino, di-C1-5alkylamino,carboxamide, amidino or guanidino;

R₂ is hydrogen or C1-3 alkyl;

R₃ is a bond, hydrogen, C1-10 alkyl, C2-10alkylene, C3-8 cycloalkyl,arylC1-5alkyl or aryl wherein R₃ is optionally substituted by one ormore R_(c);

R_(c) is C1-10 alkyl, C3-8 cycloalkyl, aryl, indanyl, indenyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, decahydronaphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl,tetrahydrothiopyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, dihydrobenzofuranyl, octohydrobenzofuranyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, C1-10 alkoxy, aryloxy, C1-10alkanoyl, aroyl, C1-10 alkoxycarbonyl, aryloxycarbonyl, C1-10alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

or R_(c) is C1-10 alkanoylamino, aroylamino, C1-10 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(c) is C1-10 alkoxycarbonylamino, aryloxycarbonylamino, C1-10alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(c) is halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino orguanidino, R_(c) may be further optionally substituted by one or moreR_(d);

R_(d) is C1-5 alkyl, C3-6 cycloalkyl, aryl, arylC1-5alkyl, C1-5 alkoxy,aryloxy, arylC1-5alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy,cyano, nitro, amidino or guanidino;

R₂ and R₃ together with the carbon they are attached optionally form anonaromatic 5-7 membered cycloalkyl or heterocyclic ring;

R₄ is hydrogen, hydroxy or C1-3 alkyl;

R₅ is a bond, hydrogen, carbonyl, C1-10 alkyl, C1-10alkoxyC1-10alkyl,C1-10alkylaminoC1-10alkyl, C1-10alkylthioC1-10alkyl wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, C1-10 alkoxy, aryloxy,C3-8 cycloalkyl, aryl, benzyl, tetrahydronaphthyl, indenyl, indanyl,C3-7cycloalkylsulfonylC1-5alkyl, arylsulfonylC1-5alkyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, thiopyranyl,tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridizinyl, tetrazolyl, triazolyl, pyrazolyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,quinazolinyl, tetrahydroquinazolinyl, benzoxazolyl and quinoxalinyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-10alkanoyl, aroyl,C1-10alkanoyloxy, benzyloxy, C1-10alkoxycarbonyl,arylC1-5alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R₅ is C1-10alkanoylamino, aroylamino, C1-10 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R₅ is C1-10 alkoxycarbonylamino, aryloxycarbonylamino, C1-10alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,arylsulfonylamino, C1-10alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R₅ is halogen, hydroxy, oxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R₅ may be further optionally substituted by one ormore R_(e);

R_(e) is C1-10 alkyl, C1-10alkoxyC1-1-alkyl, C1-10alkylaminoC1-10alkyl,C1-10alkylthioC1-10alkyl wherein the sulfur atom may be oxidized to asulfoxide or sulfone, C1-10 alkoxy, C3-8 cycloalkyl, aryl,tetrahydronaphthyl, indenyl, indanyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, thiopyranyl,tetrahydrothiopyranyl, pyranyl, tetrahydropyranyl, tetrahydrofuranyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C-1-10alkanoyl, aroyl, C1-10alkanoyloxy, aryloxy, benzyloxy, C1-10alkoxycarbonyl, arylC1-3alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(e) is C1-10 alkanoylamino, aroylamino, C1-10 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(e) is C1-10 alkoxycarbonylamino, aryloxycarbonylamino, C1-10alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(e) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(e) may be further optionally substituted by oneor more R_(f);

R_(f) is C1-5 alkyl, C3-6 cycloalkyl, tolylsulfonyl, C1-5 alkoxy, aryl,aryloxy, benzyloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro,carboxamide, amidino or guanidino;

X is O or S and

pharmaceutically acceptable derivatives thereof.

In another embodiment of the invention, there are provided novelcompounds of the formula (II) as described immediately above, andwherein:

Het is piperidinyl, pyrrolidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, azetidinyl, azepanyl, oxepanyl,tetrahydrofuranyl, oxetanyl, hexahydropyrimidinyl, hexahydropryidazinyl,piperazinyl, 1,4,5,6-tetrahydropyrimidinyl, octahydro-indolizinyl,octahydro-quinolizinyl, decahydro-quinolinyl,1,2,3,4-tetrahydro-quinolinyl, dihydrooxazolyl,1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide,isothiazolidinyl-1,1-dioxide, imidazolidinyl, pyrazolidinyl or a bridgedbicyclo chosen from aza-bicyclo[3.2.1]octane, aza-bicyclo[2.2.1]heptane,aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.2]nonane,aza-bicyclo[2.1.1]hexane, aza-bicyclo[3.1.1]heptane,aza-bicyclo[3.3.2]decane and 2-oxa or 2-thia-5-aza-bicyclo[2.2.1]heptane; each ring being substituted with one or more R₅;

Y is C(O) or S(O)₂;

R₁ is a bond, hydrogen, C1-7 alkyl, C1-7 alkoxy, C3-7 cycloalkyl,aryloxy, phenyl, benzyl, naphthyl, tetrahydronaphthyl,C1-7alkylsulfonylC1-7alkyl, C3—7cycloalkylsulfonylC1-7alkyl,arylsulfonylC 1-7alkyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,isoxazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl,benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl,benzoisoxazolyl, benzoxazolyl or amino; wherein R₁ is optionallysubstituted by one or more R_(a);

R_(a) is a bond C1-7 alkyl, C3-6 cycloalkyl, phenyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, C1-7 alkoxy, C1-7alkanoyl,C1-7alkanoyloxy, aryloxy, benzyloxy, C1-7 alkoxycarbonyl,aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-7 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(a is C)1-7 alkanoylamino, aroylamino, C1-7 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-7alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(a is C)1-7 alkoxycarbonylamino, aryloxycarbonylamino, C1-7alkylcarbamoyloxy, arylcarbamoyloxy, C1-7 alkylsulfonylamino,arylsulfonylamino, C1-7 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-7 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further optionally substituted by oneor more R_(b);

R_(b) is C1-5 alkyl, C3-6 cycloalkyl, aryl, C1-5 alkoxy, aryloxy,benzyloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino;

R₂ is hydrogen or methyl or ethyl;

R₃ is a bond, hydrogen, C1-5 alkyl, C2-5alkylene, C3-7 cycloalkyl,arylC1-3alkyl or aryl wherein R₃ is optionally substituted by one ormore R_(c);

R_(c) is C1-5 alkyl, C3-7 cycloalkyl, aryl, indanyl, indenyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, tetrahydrofuranyl,pyranyl, tetrahydropyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-5 alkoxy, aryloxy, C1-5 alkanoyl, aroyl, C1-5 alkoxycarbonyl,aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkyl,aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(c) is C1-5 alkanoylamino, aroylamino, C1-5 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-5alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(c) is C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(c) is halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino orguanidino, R_(c) may be further optionally substituted by one or moreR_(d);

R_(d) is C1-5 alkyl, C3-6 cycloalkyl, aryl, arylC1-4 alkyl, C1-5 alkoxy,aryloxy, arylC1-5alkoxy, aroyl, halogen, hydroxy, oxo or cyano;

R₄ is hydrogen or methyl;

R₅ is a bond, hydrogen, carbonyl, C1-8 alkyl, C1-8alkoxyC1-8alkyl,C1-8alkylaminoC1-8alkyl, C1-8alkylthioC1-8alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-8 alkoxy, aryloxy, C3-7cycloalkyl, aryl, benzyl, tetrahydronaphthyl, indanyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, thiopyranyl,tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, tetrazolyl,triazolyl, pyrazolyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,benzoxazolyl and quinoxalinyl, heterocyclyloxy wherein the heterocyclylmoiety is selected from those herein described in this paragraph,C1-7alkanoyl, aroyl, C1-7alkanoyloxy, benzyloxy, C1-7 alkoxycarbonyl,arylC1-4alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-7 alkyl,aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R₅ is C1-7 alkanoylamino, aroylamino, C1-7 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-7 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

or R₅ is C1-7 alkoxycarbonylamino, aryloxycarbonylamino, C1-7alkylcarbamoyloxy, arylcarbamoyloxy, C1-7 alkylsulfonylamino,arylsulfonylamino, C1-7 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-7 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R₅ is halogen, hydroxy,oxy, oxo, carboxy, cyano, nitro or carboxamide, R₅ may be furtheroptionally substituted by one or more R_(e);

R_(e) is C1-7 alkyl, C1-7alkoxyC1-7alkyl, C1-7alkylaminoC1-7alkyl,C1-7alkylthioC1-7alkyl wherein the sulfur atom may be oxidized to asulfoxide or sulfone, C1-7 alkoxy, C3-7 cycloalkyl, aryl,tetrahydronaphthyl, indanyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, thiopyranyl, tetrahydrothiopyranyl,tetrahydropyranyl, tetrahydrofuranyl, furanyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, C1-5 alkanoyl,aroyl, C1-5alkanoyloxy, aryloxy, benzyloxy, C1-5 alkoxycarbonyl,aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(e) is C1-5 alkanoylamino, aroylamino, C1-5 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-5alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(e) is C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

or R_(e) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(e) may be further optionally substituted by oneor more R_(f);

R_(f) is methyl, ethyl, t-butyl, tolylsulfonyl, C1-3 alkoxy,cyclopropyl, cyclohexyl, phenyl, naphthyl, phenoxy, benzyloxy, fluoro,chloro, bromo, hydroxy, oxo, carboxy, cyano, nitro or carboxamide;

and

X is O.

In yet another embodiment of the invention, there are provided novelcompounds of the formula (II) as described immediately above, andwherein:

wherein:

Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepanyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, oxetanyl,octahydro-indolizinyl, octahydroquinolizinyl or aza-bicyclo[3.2.1]octanyl, each ring being optionally substituted with one or more R₅;

R₁ is a bond, C1-5 alkyl, C1-5 alkoxy, C3-6 cycloalkyl, aryloxy, phenyl,benzyl, naphthyl, C1-3alkylsulfonylC1-3alkyl,C3-6cycloalkylsulfonylC1-3alkyl, arylsulfonylC1-3 alkyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, isoxazolyl,pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, benzofuranyl,benzthienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl or amino;wherein R₁ is optionally substituted by one or more R_(a);

R_(a) is a bond, C1-3 alkyl, cyclopropyl, cyclopentyl, cyclohexyl,phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, C1-3 alkoxy, C1-3alkanoyl, C1-3alkanoyloxy, aryloxy,benzyloxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

or R_(a) is C1-3 alkanoylamino, aroylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-3alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl orpiperazinyl,

or R_(a) is C1-3 alkoxycarbonylamino, aryloxycarbonylamino, C1-3alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino,arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl, or R_(a) is halogen, hydroxy, oxo,carboxy, cyano, nitro, carboxamide, amidino or guanidino, R_(a) may befurther optionally substituted by one or more R_(b);

R_(b) is C1-3 alkyl, C3-6 cycloalkyl, aryl, C1-3 alkoxy, aryloxy,benzyloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino;

R₂ is hydrogen or methyl;

R₃ is a bond, hydrogen, C1-5 alkyl, C2-5alkylene, C4-6 cycloalkyl orarylC1-2alkyl wherein R₃ is optionally substituted by one or more R_(c);

R_(c) is C1-4 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, indanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, indolinyl, furanyl, tetrahydrofuranyl, pyranyl,tetrahydropyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, C1-4 alkoxy, phenoxy, naphthyloxy, C1-3alkanoyl, benzoyl, C1-3 alkoxycarbonyl, phenoxycarbonyl, C1-3alkanoyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl or aryl,

or R_(c) is C1-3 alkanoylamino, benzoylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-5 alkyl or aryl,

or R_(c) is C1-3 alkoxycarbonylamino, aryloxycarbonylamino, C1-3alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino,arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl or aryl,

or R_(c) is halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino orguanidino, R_(c) may be further optionally substituted by one or moreR_(d);

R_(d) is C1-3 alkyl, C3-6 cycloalkyl, phenyl, benzyl, C1-3 alkoxy,phenoxy, phenylC1-3alkoxy, benzoyl, halogen, hydroxy, oxo or cyano;

R₄ is hydrogen;

R₅ is a bond, hydrogen, carbonyl, C1-6 alkyl, C1-6alkoxyC1-6alkyl,C1-6alkylaminoC1-6alkyl, C1-6alkylthioC1-6alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-6 alkoxy, phenoxy,naphthyloxy, C3-6 cycloalkyl, phenyl, naphthyl, benzyl, indanyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,furanyl, tetrahydrofuranyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl andbenzoxazolyl, heterocyclyloxy wherein the heterocyclyl moiety isselected from those herein described in this paragraph, C1-3alkanoyl,benzoyl, naphthoyl, C1-4alkanoyloxy, benzyloxy, C1-4 alkoxycarbonyl,arylC1-2alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl whereinthe nitrogen atom may be independently mono or di-substituted by C1-3alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R₅ is C1-4 alkanoylamino, aroylamino, C1-4 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-3alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl orbenzthiazolyl,

or R₅ is C1-4 alkoxycarbonylamino, phenoxycarbonylamino, C1-4alkylcarbamoyloxy, phenylcarbamoyloxy, C1-4 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-4 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

or R₅ is halogen, hydroxy, oxo, carboxy, cyano, nitro or carboxamide, R₅may be further optionally substituted by one or more R_(e);

R_(e) is C1-4 alkyl, C1-4 alkoxy, C3-7 cycloalkyl, phenyl, naphthyl,indanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, tetrahydrothiopyranyl, tetrahydropyranyl,tetrahydrofuranyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-4 alkanoyl, aroyl, C1-4alkanoyloxy, phenoxy, naphthyloxy, benzyloxy,C1-4 alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, or benzthiazolyl,

or R_(e) is C1-4 alkanoylamino, benzoylamino, C1-4 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

or R_(e) is C1-4 alkoxycarbonylamino, phenoxycarbonylamino, C1-4alkylcarbamoyloxy, phenylcarbamoyloxy, C1-4 alkylsulfonylamino,phenylsulfonylamino, C1-4 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

or R_(e) is halogen, hydroxy, oxo, carboxy, cyano, nitro or carboxamide,R_(e) may be further optionally substituted by one or more R_(f);

R_(f) is methyl, ethyl, t-butyl, tolylsulfonyl, methoxy, cyclopropyl,phenyl, phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy, oxo, carboxyor carboxamide.

In yet still another embodiment of the invention, there are providednovel compounds of the formula (II) as described immediately above, andwherein:

Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepanyl,tetrahydropyranyl, oxetanyl or tetrahydrothiopyranyl each ring beingoptionally substituted with one or more R₅;

R₁ is a bond, C1-5 alkyl, C1-5 alkoxy, C3-6 cycloalkyl, aryloxy, phenyl,benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl,quinolinyl, benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl,benzoxazolyl or amino; wherein R₁ is optionally substituted by one ormore R_(a);

R_(a) is a bond, C1-3 alkyl, cyclopropyl, cyclohexyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,thienyl, imidazolyl, C1-3 alkoxy, C1-3alkanoyl, C1-3alkanoyloxy,aryloxy, benzyloxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-3 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl or piperazinyl,

or R_(a is C)1-3 alkanoylamino, aroylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-3alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl orpiperazinyl,

or R_(a is C)1-3 alkoxycarbonylamino, aryloxycarbonylamino, C1-3alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino,arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further optionally substituted by oneor more R_(b);

R_(b) is methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, i-propoxy, phenoxy,benzyloxy, fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy, cyano,nitro or carboxamide;

R₂ is hydrogen;

R₃ is a bond, C1-3 alkyl, C2-4alkylene, C5-6 cycloalkyl, benzyl ornaphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

R_(c) is C1-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, indanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, furanyl, tetrahydropyranyl, thienyl,oxazolyl, thiazolyl, imidazolyl, pyrimidinyl, indolyl, benzofuranyl,benzothienyl, benzthiazolyl, C1-3 alkoxy, phenoxy, naphthyloxy, C1-2alkanoyl, benzoyl, C1-2 alkoxycarbonyl, phenoxycarbonyl,C1-2alkanoyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or aryl,

or R_(c) is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl or aryl,

or R_(c) is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, arylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl or phenyl,

or R_(c) is halogen, hydroxy, oxo, carboxy or cyano, R_(c) may befurther optionally substituted by one or more R_(d);

R_(d) is methyl, cyclopropyl, cyclohexyl, phenyl, benzyl, methoxy,phenoxy, benzyloxy, benzoyl, fluoro, chloro, oxo or cyano;

R₅ is a bond, hydrogen, carbonyl, C1-5 alkyl, C1-5alkoxyC1-5alkyl,C1-5alkylaminoC1-5alkyl, C1-5 alkylthioC1-5alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-5 alkoxy, phenoxy, C3-6cycloalkyl, phenyl, naphthyl, benzyl, indanyl, heterocyclyl selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl and benzthiazolyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-3alkanoyl, benzoyl, naphthoyl,C1-3alkanoyloxy, benzyloxy, C1-3 alkoxycarbonyl, benzyloxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R₅ is C1-3 alkanoylamino, aroylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzofuranyl,benzothienyl, benzimidazolyl or benzthiazolyl,

or R₅ is C1-3 alkoxycarbonylamino, phenoxycarbonylamino, C1-3alkylcarbamoyloxy, phenylcarbamoyloxy, C1-3 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

or R₅ is halogen, hydroxy, oxo, carboxy, cyano or carboxamide, R₅ may befurther optionally substituted by one or more R_(e);

R_(e) is C1-3 alkyl, C1-3 alkoxy, C3-7 cycloalkyl, phenyl, naphthyl,indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,C1-3 alkanoyl, aroyl, C1-3alkanoyloxy, phenoxy, benzyloxy, C1-3alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl orbenzthiazolyl,

or R_(e) is C1-3 alkanoylamino, benzoylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolylor benzthiazolyl,

or R_(e) is C1-3 alkoxycarbonylamino, phenoxycarbonylamino, C1-3alkylcarbamoyloxy, phenylcarbamoyloxy, C1-3 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,benzimidazolyl or benzthiazolyl,

or R_(e) is halogen, hydroxy, oxo, carboxy, cyano or carboxamide, R_(e)may be further optionally substituted by one or more R_(f);

and

R_(f) is methyl, phenyl, tolylsulfonyl, methoxy, phenoxy, benzyloxy,fluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide.

In yet still another embodiment of the invention, there are providednovel compounds of the formula (II) as described immediately above, andwherein:

Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl ortetrahydropyranyl each ring being substituted with one or more R₅;

Y is C(O);

R₁ is a bond, methyl, ethyl, i-propyl, methoxy, ethoxy, cyclopropyl,cyclopentyl, cyclohexyl, phenoxy, phenyl, benzyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, pyrazinyl or amino;wherein R₁ is optionally substituted by one or more R_(a);

R_(a) is a bond, methyl, ethyl, cyclopropyl, phenyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, thienyl,imidazolyl, methoxy, acetyl, acetoxy, phenoxy, benzyloxy,methoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl,

or R_(a) is acetylamino, benzoylamino, methylthio, phenylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by methyl,ethyl or phenyl,

or R_(a) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

or R_(a) is fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy, cyano,nitro or carboxamide, R_(a) may be further optionally substituted by oneor more R_(b);

R_(b) is methyl, cyclopropyl, phenyl, methoxy, phenoxy, benzyloxy,fluoro, chloro, hydroxy, oxo, carboxy or carboxamide;

R₃ is a bond, C1-3 alkyl, C2-4alkylene, C5-6 cycloalkyl, benzyl ornaphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

R_(c) is methyl, ethyl, n-propyl, i-propyl, C5-6 cycloalkyl, indanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, thienyl, oxazolyl, thiazolyl, indolyl,benzofuranyl, benzothienyl, benzthiazolyl, methoxy, ethoxy, phenoxy,acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by methyl, ethyl or aryl,

or R_(c) is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, phenylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by methyl, ethylor aryl,

or R_(c) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl, ethyl or phenyl,

or R_(c) is fluoro, chloro or oxo, R_(c) may be further optionallysubstituted by one or more R_(d);

R_(d) is methyl, cyclopropyl, phenyl, methoxy, fluoro, chloro or oxo;

R₅ is a bond, hydrogen, carbonyl, C1-4 alkyl, C1-4alkoxyC1-4alkyl,C1-4alkylaminoC1-4alkyl, C1-4alkylthioC1-4alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-4 alkoxy, phenoxy,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, benzyl, indanyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl and benzthiazolyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-2alkanoyl, benzoyl, naphthoyl,C1-2alkanoyloxy, benzyloxy, C1-2 alkoxycarbonyl, benzyloxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R₅ is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolylor benzthiazolyl,

or R₅ is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, phenylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R₅ is fluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide, R₅may be further optionally substituted by one or more R_(e);

R_(e) is C1-3 alkyl, C1-2 alkoxy, C3-6 cycloalkyl, phenyl, naphthyl,indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,C1-2 alkanoyl, aroyl, C1-2alkanoyloxy, phenoxy, benzyloxy, C1-2alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-2 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R_(e) is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R_(c) is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, phenylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-2 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R_(e) is fluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide,R_(e) may be further optionally substituted by one or more R_(f); and

R_(f) is methyl, phenyl, tolylsulfonyl, methoxy, phenoxy, benzyloxy,fluoro, chloro, hydroxy, oxo, carboxy or carboxamide.

In yet a further embodiment of the invention, there are provided novelcompounds of the formula (II) as described immediately above, andwherein:

Het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl, azetidin-3-yl,azepan-3-yl, azepan-4-yl or tetrahydropyran-4-yl, each ring beingoptionally substituted with one or more R₅;

R₁ is a bond, methyl, ethyl, i-propyl, methoxy, cyclopropyl, cyclohexyl,phenoxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, thiazolyl,imidazolyl, pyridinyl, pyrazinyl or amino; wherein R₁ is optionallysubstituted by one or more R_(a);

R_(a) is methyl, phenyl, thienyl, methoxy, acetyl, acetoxy, phenoxy,benzyloxy, methoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogenatom may be independently mono or di-substituted by methyl or phenyl,

or R_(a) is acetylamino, methylthio, phenylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl or phenyl,

or R_(a) is methoxycarbonylamino, methylcarbamoyloxy,phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

or R_(a) is fluoro, chloro, hydroxy, oxo, carboxy, cyano or carboxamide;

R₃ is a bond, methyl, ethyl, n-propyl, propenyl, butenyl, i-butenyl,cyclohexyl, benzyl or naphthylmethyl wherein R₃ is optionallysubstituted by one or more R_(c);

R_(c) is methyl, ethyl, n-propyl, i-propyl, cyclohexyl, cyclopentyl,indanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl,bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl,cubanyl, 1,2,3,4-tetrahydronaphthyl, methoxy, phenoxy, acetyl, benzoyl,methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy, methylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, fluoro, chloro or oxo;

R₅ is a bond, hydrogen, carbonyl, C1-4 alkyl, C1-2alkoxyC1-2alkyl,C1-2alkylaminoC1-2alkyl, C1-2alkylthioC1-2alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-2 alkoxy, phenoxy,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl,pyridinyl, and pyrimidinyl, heterocyclyloxy wherein the heterocyclylmoiety is selected from those herein described in this paragraph,acetyl, benzoyl, acetyloxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl,benzyloxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom maybe independently mono or di-substituted by methyl, ethyl or phenyl,

or R₅ is acetylamino, benzoylamino, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl orphenyl,

or R₅ is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

or R₅ is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R₅ may befurther optionally substituted by one or more R_(e);

R_(e) is methyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl,phenyl, naphthyl, indanyl, piperidinyl, morpholinyl, indolyl, thienyl,pyridinyl, acetyl, benzoyl, acetyloxy, phenoxy, benzyloxy,methoxycarbonyl, ethoxycarbonyl, carbamoyl wherein the nitrogen atom maybe independently mono or di-substituted by methyl, ethyl or phenyl,

or R_(e) is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, phenylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by methyl, ethylor phenyl,

or R_(e) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

or R_(e) is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R_(e)may be further optionally substituted by one or more R_(f);

and

R_(f) is methyl, phenyl, tolylsulfonyl, phenoxy, benzyloxy, fluoro,chloro or oxo.

In yet still a further embodiment of the invention, there are providednovel compounds of the formula (II) as described immediately above, andwherein:

Het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl, azetidin-3-yl ortetrahydropyran-4-yl, each ring being substituted with one or more R₅;

R₁ is i-propyl, benzyloxy, cyclohexyl, phenyl, 4-(acetylamino)-phenyl,4-(methanesulfonylamino)-phenyl, 4-methoxyphenyl, 3-phenoxyphenyl,4-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl,naphthyl, thienylmethyl, piperidinyl, morpholinyl, pyrrolidinyl,piperazinyl, furanyl, thienyl, 5-chlorothienyl, pyridin-4-yl, pyrazinyl,methylamino, ethylamino, dimethylamino or diethylamino;

R₃ is ethyl, n-propyl,propenyl, butenyl, i-butenyl, benzyl ornaphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

R_(c) is methyl, cyclohexyl, cyclopentyl, indanyl,1,2,3,4-tetrahydronaphthyl, methoxy, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, fluoro or chloro;

R₅ is a bond, carbonyl, methyl, ethyl, n-propyl, n-butyl, t-butyl,i-propyl, i-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl,piperidinyl, tetrahydropyranyl, pyrimidinyl, acetyl, benzoyl,ethoxycarbonyl, benzyloxycarbonyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxo or carboxy,R₅ may be further optionally substituted by one or more R_(e);

R_(e) is methyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl,indanyl, thienyl, 5-methylthienyl, methoxy, phenoxy, benzyloxy,piperidinyl, pyridinyl, indolyl, 1-(tolyl-sulfonyl)-indolyl, carbamoylwherein the nitrogen atom may be independently mono or di-substituted bymethyl, phenyl or benzyl,

or R_(e) is hydroxy, fluoro, chloro, oxo, dimethylamino ortrifluoromethyl;

In yet another embodiment of the invention, there are provided novelcompounds of the formula (II) as described immediately above, andwherein:

Het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl or azetidin-3-yl,each ring being substituted with one or more R₅;

R₁ is phenyl, 4-(acetylamino)-phenyl, 4-(methanesulfonylamino)-phenyl,3-phenoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, thienylmethyl,morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, 5-chlorothienyl,pyridin-4-yl or pyrazinyl;

R₃ is n-butyl, i-butyl, 2,2-dimethylpropyl, cyclohexylmethyl, propenyl,i-butenyl, 4-methoxybenzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl,3-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylbenzyl, 3-methylbenzyl ornaphth-2-ylmethyl; wherein the configuration at the stereocenter definedby R₂ and R₃ when they are different and the carbon they are attached tois defined as L; and

R₅ is a bond, methyl, ethyl, n-propyl, n-butyl, n-pentyl, 2-pentyl,3-pentyl, phenethyl, phenpropyl, 2,2-dimethylpropyl, t-butyl, i-propyl,i-butyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, naphthylmethyl,indanylmethyl, pyridinylmethyl, indolylmethyl, thienylmethyl,5-methylthienylmethyl, piperidinyl, piperidinylcarbonyl,pyridinylcarbonyl, tetrahydropyranyl, pyrimidinyl, acetyl, benzoyl,ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, methylcarbamoyl,phenylcarbamoyl, benzylcarbamoyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, methylcyclohexyl,methylbenzyl, methoxybenzyl, phenoxybenzyl, benzyloxybenzyl,N-[(4-methylphenyl)-sulfonyl]-indolylmethyl, fluorobenzyl,difluorobenzyl, chlorobenzyl, N,N-dimethylaminoacetyl,trifluoromethylbenzyl, fluoro, oxo or carboxy.

Another embodiment of the invention provides for the following compoundsof the formulas (I) and (II) above which have demonstrated potentinhibition of Cathepsin S in a cell based assay at concentrations of 15uM or less.

Morpholine-4-carboxylic acid[1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

4-Acetylamino-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;

4-Acetylamino-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-benzamide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

4-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicacid t-butyl ester;

4-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicacid ethyl ester;

Morpholine-4-carboxylic acid[1-(1-benzyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidehydrochloride;

Morpholine-4-carboxylic acid{1-[4-cyano-1-(1-methyl-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

4-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicacid benzyl ester;

Morpholine-4-carboxylic acid[1-(4-cyano-1-isopropyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(1-phenethyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(1-n-propyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-tetrahydro-thiopyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[4-cyano-1-(2-dimethylamino-acetyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

4-Cyano-4-{3-cyclohexyl-2-[({4-acetylamino}-phenyl-1-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicacid ethyl ester;

Morpholine-4-carboxylic acid[1-(3-cyano-1-pyrimidin-2-yl-piperidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

4-Cyano-4-{4,4-dimethyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicacid benzyl ester;

4-Acetylamino-N-[1-(1-benzyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;

4-Acetylamino-N-[1-(4-cyano-1-isopropyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-piperidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

4-Cyano-4-{3-cyclohexyl-2-[({4-acetylamino}-phenyl-1-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicacid benzyl ester;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;

Morpholine-4-carboxylic acid[1-(1-carbamimidoyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidep-toluenesulfonate;

4-Acetylamino-N-[1-(4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;

4-(Acetylamino-methyl)-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;

4-Cyano-4-{4,4-dimethyl-2-[(morpholine-4-carbonyl)-amino]-pentanoylamino}-piperidine-1-carboxylicacid ethyl ester;

Morpholine-4-carboxylic acid[1-(1-acetyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide:,

Morpholine-4-carboxylic acid[1-(1-benzoyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

3-Cyano-3-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-pyrrolidine-1-carboxylicacid benzyl ester;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-isonicotinamide;

Pyrazine-2-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(1-acetyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(1-benzoyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2-chloro-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

5-Chloro-thiophene-2-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

4-Chloro-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-phenylcarbamoyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid [1-(1-benzylcarbamoyl4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-4-methanesulfonylamino-benzamide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-3-phenoxy-benzamide;

N-[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl-ethyl]-isonicotinamide;

Pyrazine-2-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-3-cyclohexyl-2-(2-thiophen-2-yl-acetylamino)-propionamide;

5-Chloro-thiophene-2-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(cyclohexyl-methyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

N-[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-3-phenoxy-benzamide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

N-[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-4-chloro-benzamide;

N-[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-benzamide;

Pyrazine-2-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-methyl-ethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

N-[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-4-methanesulfonylamino-benzamide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(3-benzyloxy-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

N-[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl-2-cyclohexyl-ethyl]-benzamide;

N-[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-4-methanesulfonylamino-benzamide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2-benzyloxy-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-benzamide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(3,5-difluoro-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2,6-difluoro-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(3-trifluoromethyl-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-2-fluoro-benzamide;

4-Chloro-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-2-fluoro-benzamide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-4-methoxy-benzamide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-4-fluoro-benzamide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-4-methanesulfonylamino-benzamide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(3-phenoxy-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-methyl-piperidine-4-yl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-methyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(3-methyl-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2-phenoxy-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2-methyl-pent-2-enyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(4-fluoro-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2,4,6-trimethyl-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1H-indol-3-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopropyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-pyridin-3-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Pyrrolidine-1-carboxylic acid[-1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-1-oxy-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Isoxazole-5-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-isobutyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

1H-Imidazole-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(5,5-dimethyl-3-oxo-cyclohex-1-enyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-isopropyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-isobutyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butyl}-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-phenethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopropylmethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-methyl-piperidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-azetidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

4-Cyano-4-{3-cyclohexyl-2-[(4-methyl-piperazine-1-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicacid ethyl ester;

Morpholine-4-carboxylic acid[1-(3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(trans-4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(cis-4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

N-[4-Cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-isonicotinamide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopentyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-isobutyl-piperidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopentyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(cis-4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butyl}-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(trans-4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butyl}-amide;

Morpholine-4-carboxylic acid(1-{3-cyano-1-[1-(toluene-4-sulfonyl)-1H-indol-3-ylmethyl]-pyrrolidin-3-ylcarbamoyl}-2-cyclohexyl-ethyl)-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexyl-pyrrolidin-3-ylcarbamoyl)-2-(4-iodo-phenyl)-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexyl-pyrrolidin-3-ylcarbamoyl)-2-p-tolyl-ethyl]-amide;

Morpholine-4-carboxylic acid[(3-cyano-1-cyclohexyl-pyrrolidin-3-ylcarbamoyl)-cyclohexyl-methyl]-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-naphthalen-2-yl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-(4-chloro-phenyl)-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(indan-2-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

1-Benzyl-3-cyano-3-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-pyrrolidine-2-carboxylicacid methyl ester;

N[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-isobutyramide;

[1-Benzyl-3-cyno-pyrrolidin-3-ylcarbomoyl)-2-cyclohexyl-ethyl]-carbonicacid benzyl ester;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-but-3-enyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(3-methoxy-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(naphthalen-2-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Cyclohexanecarboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopentylmethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[4-cyano-1-(1-methyl-piperidine-4-carbonyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[4-cyano-1-(pyridine-4-carbonyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-2-hydroxymethyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;

4-Chloro-N-[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-benzamide;

Pyrazine-2-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

4,4-dimethyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-[(morpholine-4-carbothioyl)-amino]-propionamide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid{1-[4-cyano-1-(tetrahydro-pyran-4-yl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide;.

Morpholine-4-carboxylic acid[2-(4-chloro-phenyl)-1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-naphthalen-2-yl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3-methyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1,2-dimethyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Naphthalene-2-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;

and the pharmaceutically acceptable derivatives thereof.

The following are preferred compounds of the formulas (I) and (II) ofthe invention:

Morpholine-4-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

4-Acetylamino-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;

4-Acetylamino-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-benzamide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidehydrochloride;

Morpholine-4-carboxylic acid{1-[4-cyano-1-(1-methyl-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-isopropyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(1-phenethyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(1-n-propyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

4-Acetylamino-N-[1-(1-benzyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;4-Acetylamino-N-[1-(4-cyano-1-isopropyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-piperidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;

4-(Acetylamino-methyl)-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-isonicotinamide;

Pyrazine-2-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

5-Chloro-thiophene-2-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

4-Chloro-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-3-phenoxy-benzamide;

N-[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl-ethyl]-isonicotinamide;

Pyrazine-2-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(cyclohexyl-methyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

N-[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-benzamide;

Pyrazine-2-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-methyl-ethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

N-[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-4-methanesulfonylamino-benzamide;

N-[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-4-methanesulfonylamino-benzamide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-benzamide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-4-fluoro-benzamide;

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-4-methanesulfonylamino-benzamide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-methyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(3-methyl-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2-methyl-pent-2-enyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1H-indol-3-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Pyrrolidine-1-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-isobutyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-isopropyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-isobutyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butyl}-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-phenethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopropylmethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-methyl-piperidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-azetidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(trans-4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopentyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-isobutyl-piperidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopentyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(trans-4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butyl}-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-naphthalen-2-yl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-(4-chloro-phenyl)-ethyl]-amide;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-but-3-enyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopentylmethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;

4-Chloro-N-[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-benzamide;

Pyrazine-2-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

4,4-dimethyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

Morpholine-4-carboxylic acid[2-(4-chloro-phenyl)-1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-naphthalen-2-yl-ethyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3-methyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1,2-dimethyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;

and the pharmaceutically acceptable derivatives thereof.

The activity of particular compounds disclosed herein against cathepsinK may be determined without undue experimentation by one of ordinaryskill in the art in view of the art, the guidance provided throughoutthis specification and by the screens described in the section entitled“Assessment of Biological Properties.”

The following subgeneric aspect of the compounds of the formula (II)have Cathepsin K activity:

The compound according to the third embodiment above of formula (II) andwherein:

Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepanyl,tetrahydropyranyl, oxetanyl or tetrahydrothiopyranyl each ring beingoptionally substituted with one or more R₅;

R₁ is a bond, C1-4 alkyl, C1-4 alkoxy, cyclopropyl, cyclohexyl, phenoxy,naphthyloxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,indolyl, quinolinyl, benzofuranyl, benzthienyl, benzimidazolyl,benzthiazolyl, benzoxazolyl or amino; wherein R₁ is optionallysubstituted by one or more R_(a);

R_(a) is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclohexyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, thienyl, imidazolyl, methoxy, ethoxy, acetyl, acetoxy,phenoxy, naphthyloxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl,phenoxycarbonyl, naphthyloxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

or R_(a) is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ethylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

or R_(a) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, C1-2 alkylcarbamoyloxy, phenylcarbamoyloxy,naphthylcarbamoyloxy, C1-2 alkylsulfonylamino, phenylsulfonylamino,naphthylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl,naphthylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl, phenyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,

or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further optionally substituted by oneor more R_(b);

R_(b) is methyl, ethyl, cyclopropyl, cyclohexyl, phenyl, methoxy,ethoxy, phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy, oxo,carboxy, cyano, nitro or carboxamide;

R₂ is hydrogen or methyl;

R₃ is a bond, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,n-pentyl, propenyl, i-butenyl, cyclohexyl, benzyl or naphthylmethylwherein R₃ is optionally substituted by one or more R_(c);

R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl, naphthyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl, furanyl,tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyrimidinyl, methoxy, ethoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl,phenoxycarbonyl, acetoxy, benzoyloxy, carbamoyl wherein the nitrogenatom may be independently mono or di-substituted by methyl or phenyl,

or R_(c) is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, phenylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by methyl orphenyl,

or R_(c) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

or R_(c) is chloro, fluoro, hydroxy, oxo, carboxy or cyano;

R₂ and R₃ together with the carbon they are attached optionally form aring selected from cyclopentyl, cyclohexyl, cycloheptyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl ortetrahydrothiophenyl;

R₄ is hydrogen;

R₅ is a bond, hydrogen, carbonyl, C1-5 alkyl, C1-5alkoxyC1-5alkyl,C1-5alkylaminoC1-5alkyl, C1-5alkylthioC1-5alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-5 alkoxy, phenoxy,naphthyloxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,tetrahydropyranyl, pyridinyl, and pyrimidinyl, heterocyclyloxy whereinthe heterocyclyl moiety is selected from those herein described in thisparagraph, acetyl, benzoyl, acetyloxy, benzyloxy, methoxycarbonyl,ethoxycarbonyl, benzyloxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl,

or R₅ is acetylamino, benzoylamino, phenylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl orphenyl,

or R₅ is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,phenylsulfonylamino, phenylaminosulfonyl, amino wherein the nitrogenatom may be independently mono or di-substituted by methyl, ethyl orphenyl,

or R₅ is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R₅ may befurther optionally substituted by one or more R_(e);

R_(e) is methyl ethyl, methoxy, ethoxy, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, naphthyl, indanyl, piperidinyl, morpholinyl,indolyl, thienyl, pyridinyl, methoxy, ethoxy, acetyl, benzoyl,acetyloxy, phenoxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by methyl, ethyl or phenyl,

or R_(e) is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, phenylthio methylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl or phenyl,

or R_(e) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

or R_(e) is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R_(e)may be further optionally substituted by one or more R_(f);

R_(f) is methyl, phenyl, tolylsulfonyl, phenoxy, benzyloxy, fluoro,chloro or oxo.

Another embodiment of the compounds of the formula (II) having CathepsinK activity are those described immediately above and wherein:

R₁ is a bond, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy,benzyloxy, cyclopropyl, cyclohexyl, phenoxy, naphthyloxy, phenyl,benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl,quinolinyl, benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl,benzoxazolyl or amino; wherein R₁ is optionally substituted by one ormore R_(a);

R_(a) is methyl, cyclopropyl, phenyl, halogen, hydroxy, oxo, carboxy,cyano, nitro or carboxamide;

R₃ is a bond, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,n-pentyl, propenyl, i-butenyl, benzyl or naphthylmethyl wherein R₃ isoptionally substituted by one or more R_(c);

R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl, furanyl,tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, methoxy, phenoxy,acetyl, benzoyl, methoxycarbonyl, carbamoyl wherein the nitrogen atommay be independently mono or di-substituted by methyl or phenyl,

or R_(c) is acetylamino, benzoylamino, methylthio, methoxycarbonylamino,methylcarbamoyloxy, methylsulfonylamino, methylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl,

or R_(c) is fluoro or oxo;

R₂ and R₃ together with the carbon they are attached optionally form aring selected from cyclopentyl, cyclohexyl, cycloheptyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,pyrrolidinyl or piperidinyl;

R₅ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, 2-pentyl, 3-pentyl,phenethyl, phenpropyl, 2,2-dimethylpropyl, t-butyl, i-propyl, i-butyl,cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, 2-methylbenzyl,3-methylbenzyl, 4-methylbenzyl, 2,6-dimethylbenzyl, 2,5-dimethylbenzyl,2,4-dimethylbenzyl, 2,3-dimethylbenzyl, 3,4-dimethylbenzyl,3,5-dimethylbenzyl, 2,4,6-trimethylbenzyl, 2-methoxybenzyl,3-methoxybenzyl, 4-methoxybenzyl, 2-phenoxybenzyl, 3-phenoxybenzyl,4-phenoxybenzyl, 2-benzyloxybenzyl, 3-benzyloxybenzyl,4-benzyloxybenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,2,6-difluorobenzyl, 2,5-difluorobenzyl, 2,4-difluorobenzyl,2,3-difluorobenzyl, 3,4-difluorobenzyl, 3,5-difluorobenzyl,2,4,6-triflurobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, naphthylmethyl, indanylmethyl, pyridinylmethyl,indolylmethyl, thienylmethyl, 5-methylthienylmethyl, piperidinyl,piperidinylcarbonyl, pyridinylcarbonyl, tetrahydropyranyl, pyrimidinyl,acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl,methylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxo or carboxy.

Yet another embodiment of the compounds of the formula (II) havingCathepsin K activity are those described immediately above and wherein:

R₁ is methoxy, benzyloxy, cyclohexyl, phenoxy, naphthyloxy, phenyl,benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl,benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl, benzoxazolylor amino; wherein R₁ is optionally substituted by one or more R_(a);

R_(a) is methyl, phenyl, fluoro, chloro, hydroxy, oxo, carboxy orcarboxamide;

R₃ is a bond, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,n-pentyl, propenyl, i-butenyl or benzyl wherein R₃ is optionallysubstituted by one or more R_(c);

R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl, furanyl,tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, methoxy, phenoxy,acetyl, benzoyl, methoxycarbonyl, acetylamino, methylthio,methylsulfonylamino or fluoro;

R₂ and R₃ together with the carbon they are attached optionally form aring selected from cyclopentyl, cyclohexyl, cycloheptyl,tetrahydropyranyl, tetrahydrothiopyranyl or tetrahydrofuranyl;

R₅ is methyl, ethyl, n-propyl, n-butyl, phenethyl, phenpropyl, t-butyl,i-propyl, i-butyl, cyclopropyl, cyclohexyl, cyclopropylmethyl,cyclohexylmethyl, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl,4-methoxybenzyl 4-fluorobenzyl, 3,5-difluorobenzyl,4-trifluoromethylbenzyl, naphthylmethyl, pyridinylmethyl, indolylmethyl,thienylmethyl, acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl,t-butoxycarbonyl, phenylcarbamoyl, phenylsulfonylamino or fluoro.

Yet still another embodiment of the compounds of the formula (II) havingCathepsin K activity are those described immediately above and wherein:

Het is pyrrolidinyl, piperidinyl or tetrahydropyranyl;

R₁ is benzyloxy, phenoxy, naphthyloxy, phenyl, naphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyridinyl,indolyl, quinolinyl, benzofuranyl, benzthienyl, benzimidazolyl,benzthiazolyl, benzoxazolyl or phenylamino;

R₃ is n-propyl, i-butyl, propenyl, i-butenyl or 2,2-dimethylpropyl;

R₂ and R₃ together with the carbon they are attached optionally form aring selected from cyclopentyl, cyclohexyl, or cycloheptyl;

R₅ is methyl, ethyl, n-propyl, phenethyl, t-butyl, i-propyl, i-butyl,cyclohexyl, cyclohexylmethyl, benzyl, 4-fluorobenzyl, naphthylmethyl,acetyl, benzoyl or benzyloxycarbonyl.

Representative compounds possessing CAT K activity are the following:

[1-(1-Benzyl-4-cyano-piperidin-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid benzyl ester;

[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-cyclohexyl]-carbamic acidt-butyl ester;

[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-3-methyl-butyl]-carbamicacid benzyl ester;

[-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-cyclohexyl]-carbamic acidbenzyl ester;

Naphthalene-2-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3-methyl-butyl]-amide;

Naphthalene-2-carboxylic acid[1-(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;

[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-carbamicacid benzyl ester;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;

[1-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-carbamicacid benzyl ester;

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-but-3-enyl]-amide.

In a third broad generic aspect of the invention, there are providednovel compounds of the formulas (Ia) and (Ib):

wherein:

Het is

azepanyl, piperidinyl, pyrrolidinyl, azetidinyl, oxepanyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, oxetanyl,azocanyl, oxocanyl, 1,3-diazocanyl, 1,4-diazocanyl, 1,5-diazocanyl,1,3-dioxocanyl, 1,4-dioxocanyl, 1,5-dioxocanyl, 1,3-oxazocanyl,1,4-oxazocanyl, 1,5-oxazocanyl, 1,3-diazepanyl, 1,4-diazepanyl,1,3-dioxepanyl, 1,4-dioxepanyl, 1,3-oxazepanyl, 1,4-oxazepanyl,1,2-thiazocanyl-1,1-dioxide, 1,2,8-thiadiazocanyl-1,1-dioxide,1,2-thiazepanyl-1,1-dioxide, 1,2,7-thiadiazepanyl-1,1-dioxide,tetrahydrothiophenyl, hexahydropyrimidinyl, hexahydropyridazinyl,piperazinyl, 1,4,5,6-tetrahydropyrimidinyl, pyrazolidinyl,dihydrooxazolyl, dihydrothiazolyl, dihydroimidazolyl, isoxazolinyl,oxazolidinyl, 1,2-thiazinanyl-1,1-dioxide,1,2,6-thiadiazinanyl-1,1-dioxide, isothiazolidinyl-1,1-dioxide,imidazolidinyl-2,4-dione, imidazolidinyl, morpholinyl, dioxanyl,tetrahydropyridinyl, thiomorpholinyl, thiazolidinyl, dihydropyranyl,dithianyl, decahydro-quinolinyl, decahydro-isoquinolinyl,1,2,3,4-tetrahydro-quinolinyl, indolinyl, octahydro-quinolizinyl,dihydro-indolizinyl, octahydro-indolizinyl, octahydro-indolyl,decahydroquinazolinyl, decahydroquinoxalinyl,1,2,3,4-tetrahydroquinazolinyl or 1,2,3,4-tetrahydroquinoxalinyl;

A C6-C10 bridged bicyclo wherein one or more carbon atoms are optionallyreplaced by a heteroatom chosen from N, O and S;

each being optionally substituted with one or more R₅;

R₁ is a bond, hydrogen, C1-10 alkyl, C1-10 alkoxy, aryloxy, C3-8cycloalkyl, C3-8 cycloalkyloxy, aryl, benzyl, tetrahydronaphthyl,indenyl, indanyl, C1-10alkylsulfonylC1-10alkyl,C3-8cycloalkylsulfonylC1-10alkyl, arylsulfonylC1-10alkyl, heterocyclylselected from azepanyl, azocanyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl,tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl,pyrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, benzisoxazolyl, quinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl,tetrahydroquinazolinyl, benzoxazolyl and quinoxalinyl, heterocyclyloxywherein the heterocyclyl moiety is selected from those herein describedin this paragraph, hydroxy or amino; wherein R₁ is optionallysubstituted by one or more R_(a);

R_(a) is a bond, C1-10 alkyl, C3-8 cycloalkyl, aryl, tetrahydronaphthyl,indenyl, indanyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, C1-10 alkoxy, C1-10alkanoyl,C1-10alkanoyloxy, aryloxy, benzyloxy, C1-10 alkoxycarbonyl,aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

or R_(a) is C1-10 alkanoylamino, aroylamino, C1-10 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(a) is C1-10 alkoxycarbonylamino, aryloxycarbonylamino, C1-10alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further optionally substituted by oneor more R_(b); with the proviso that R₁ and R_(a) simultaneously cannotbe a bond;

R_(b) is a C1-6 saturated or unsaturated branched or unbranched carbonchain optionally partially or fully halogenated wherein one or morecarbon atoms are optionally replaced by O, N, S(O), S(O)₂ or S andwherein said chain is optionally independently substituted with 1-2 oxogroups, —NH₂, or one or more C1-4 alkyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl;

or R_(b) is C3-6 cycloalkyl, aryl, aryloxy, benzyloxy, halogen, hydroxy,oxo, carboxy, cyano, nitro, mono-C1-5alkylamino, di-C1-5alkylamino,carboxamide, amidino or guanidino;

R₂ is hydrogen or C1-3 alkyl;

R₃ is a bond, hydrogen, C1-10alkyl, C2-10alkylene, C3-8 cycloalkyl,arylC1-5alkyl or aryl wherein R₃ is optionally substituted by one ormore R_(c);

R_(c) is C1-10 alkyl, C3-8 cycloalkyl, aryl, indanyl, indenyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, decahydronaphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl,tetrahydrothiopyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, dihydrobenzofuranyl, octohydrobenzofuranyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, C1-10 alkoxy, aryloxy, C1-10alkanoyl, aroyl, C1-10 alkoxycarbonyl, aryloxycarbonyl, C1-10alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

or R_(c) is C1-10 alkanoylamino, aroylamino, C1-10 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(c) is C1-10 alkoxycarbonylamino, aryloxycarbonylamino, C1-10alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(c) is halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino orguanidino, R_(c) may be further optionally substituted by one or moreR_(d);

R_(d) is C1-5 alkyl, C3-6 cycloalkyl, aryl, arylC1-5alkyl, C1-5 alkoxy,aryloxy, arylC1-5alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy,cyano, nitro, amidino or guanidino;

R₂ and R₃ together with the carbon they are attached optionally form anonaromatic 5-7 membered cycloalkyl or heterocyclic ring;

each R₄ is independently hydrogen, hydroxy or C1-3 alkyl;

R₅ is a bond, hydrogen, carbonyl, C1-10 alkyl, C1-10alkoxyC1-10alkyl,C1-10alkylaminoC1-10alkyl, C1-10alkylthioC1-10alkyl wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, C1-10 alkoxy, aryloxy,C3-8 cycloalkyl, aryl, benzyl, tetrahydronaphthyl, indenyl, indanyl,C3-7cycloalkylsulfonylC1-5alkyl, arylsulfonylC1-5alkyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, thiopyranyl,tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridizinyl, tetrazolyl, triazolyl, pyrazolyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,quinazolinyl, tetrahydroquinazolinyl, benzoxazolyl and quinoxalinyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-10alkanoyl, aroyl,C1-10alkanoyloxy, benzyloxy, C1-10alkoxycarbonyl,arylC1-5alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R₅ is C1-10 alkanoylamino, aroylamino, C1-10 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R₅ is C1-10 alkoxycarbonylamino, aryloxycarbonylamino, C1-10alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R₅ is halogen, hydroxy, oxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R₅ may be further optionally substituted by one ormore R_(e);

R_(e) is C1-10alkyl, C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl,C1-10alkylthioC1-10alkyl wherein the sulfur atom may be oxidized to asulfoxide or sulfone, C1-10 alkoxy, C3-8 cycloalkyl, aryl,tetrahydronaphthyl, indenyl, indanyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, thiopyranyl,tetrahydrothiopyranyl, pyranyl, tetrahydropyranyl, tetrahydrofuranyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-10alkanoyl, aroyl, C1-10alkanoyloxy, aryloxy, benzyloxy, C1-10alkoxycarbonyl, arylC1-3alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(e) is C1-10 alkanoylamino, aroylamino, C1-10 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(e) is C1-10 alkoxycarbonylamino, aryloxycarbonylamino, C1-10alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(e) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(e) may be further optionally substituted by oneor more R_(f);

R_(f) is C1-5 alkyl, C3-6 cycloalkyl, tolylsulfonyl, C1-5 alkoxy, aryl,aryloxy, benzyloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro,carboxamide, amidino or guanidino;

R₆ is

hydrogen, hydroxy, nitrile or

a C1-6 saturated or unsaturated branched or unbranched carbon chainoptionally partially or fully halogenated wherein one or more C atomsare optionally replaced by O, NH, S(O), S(O)₂ or S and wherein saidchain is optionally independently substituted with 1-2 oxo groups, —NH₂,one or more C₁₄ alkyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,benzoxazolyl or quinoxalinyl;

wherein R₁ and R₆ in the formulas (Ia) or (Ib) optionally form a 4 to 8membered mono- or 7-12 membered polycyclo heteroring system, eacharomatic or nonaromatic, wherein each heteroring is optionallysubstituted by one or more R₇;

each R₇ and R₈ are independently:

C1-5 alkyl chain optionally interrupted by one or two N, O or S(O)_(m)and optionally substituted by 1-2 oxo, amino, hydroxy, halogen,C1-4alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,benzoxazolyl or quinoxalinyl,

aryl, aryloxy, aroyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyridinyl,pyrimidinyl, C1-5 alkanoyl, C1-5 alkoxycarbonyl, aryloxycarbonyl,benzyloxycarbonyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio,arylthio C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, C3-6 cycloalkyl and benzyloxy

each of the aforementioned are optionally halogenated,

halogen, hydroxy, oxo, carboxy, nitrile, nitro or NH₂C(O)—;

m is 0, 1 or 2;

X is ═O, ═S or ═N—R₆ wherein R₆ is as defined above, and

pharmaceutically acceptable derivatives thereof.

In another embodiment of the invention, there are provided novelcompounds of the formula (Ia) and formula (Ib) as described immediatelyabove, and wherein:

Het is piperidinyl, pyrrolidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, azetidinyl, azepanyl, oxepanyl,tetrahydrofuranyl, oxetanyl, hexahydropyrimidinyl, hexahydropryidazinyl,piperazinyl, 1,4,5,6-tetrahydropyrimidinyl, octahydro-indolizinyl,octahydro-quinolizinyl, decahydro-quinolinyl,1,2,3,4-tetrahydro-quinolinyl, dihydrooxazolyl,1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide,isothiazolidinyl-1,1-dioxide, imidazolidinyl, pyrazolidinyl or a bridgedbicyclo chosen from aza-bicyclo[3.2.1]octane, aza-bicyclo[2.2.1]heptane,aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.2]nonane,aza-bicyclo[2.1.1]hexane, aza-bicyclo[3.1.1]heptane,aza-bicyclo[3.3.2]decane and 2-oxa or2-thia-5-aza-bicyclo[2.2.1]heptane; each ring being substituted with oneor more R₅;

R₁ is a bond, hydrogen, C1-7 alkyl, C1-7 alkoxy, C3-7 cycloalkyl,aryloxy, phenyl, benzyl, naphthyl, tetrahydronaphthyl,C1-7alkylsulfonylC1-7alkyl, C3-7cycloalkylsulfonylC1-7alkyl,arylsulfonylC1-7alkyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,isoxazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl,benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl,benzoisoxazolyl, benzoxazolyl or amino; wherein R₁ is optionallysubstituted by one or more R_(a);

R_(a) is a bond C1-7 alkyl, C3-6 cycloalkyl, phenyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, C1-7 alkoxy, C1-7alkanoyl,C1-7alkanoyloxy, aryloxy, benzyloxy, C1-7 alkoxycarbonyl,aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-7 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(a) is C1-7 alkanoylamino, aroylamino, C1-7 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-7alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(a) is C1-7 alkoxycarbonylamino, aryloxycarbonylamino, C1-7alkylcarbamoyloxy, arylcarbamoyloxy, C1-7 alkylsulfonylamino,arylsulfonylamino, C1-7 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-7 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further optionally substituted by oneor more R_(b);

R_(b) is C1-5 alkyl, C3-6 cycloalkyl, aryl, C1-5 alkoxy, aryloxy,benzyloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino;

R₂ is hydrogen or methyl or ethyl;

R₃ is a bond, hydrogen, C1-5 alkyl, C2-5alkylene, C3-7 cycloalkyl,arylC1-3alkyl or aryl wherein R₃ is optionally substituted by one ormore R_(c);

R_(c) is C1-5 alkyl, C3-7 cycloalkyl, aryl, indanyl, indenyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, tetrahydrofuranyl,pyranyl, tetrahydropyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-5 alkoxy, aryloxy, C1-5 alkanoyl, aroyl, C1-5 alkoxycarbonyl,aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkyl,aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(c) is C1-5 alkanoylamino, aroylamino, C1-5 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-5alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(c) is C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofiranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(c) is halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino orguanidino, R_(c) may be further optionally substituted by one or moreR_(d);

R_(d) is C1-5 alkyl, C3-6 cycloalkyl, aryl, arylC1-4 alkyl, C1-5 alkoxy,aryloxy, arylC1-5alkoxy, aroyl, halogen, hydroxy, oxo or cyano;

R₄ is hydrogen or methyl;

R₅ is a bond, hydrogen, carbonyl, C1-8 alkyl, C1-8alkoxyC1-8alkyl,C1-8alkylaminoC1-8alkyl, C1-8alkylthioC1-8alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-8 alkoxy, aryloxy, C3-7cycloalkyl, aryl, benzyl, tetrahydronaphthyl, indanyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, thiopyranyl,tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, tetrazolyl,triazolyl, pyrazolyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,benzoxazolyl and quinoxalinyl, heterocyclyloxy wherein the heterocyclylmoiety is selected from those herein described in this paragraph,C1-7alkanoyl, aroyl, C1-7alkanoyloxy, benzyloxy, C1-7 alkoxycarbonyl,arylC1-4alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-7 alkyl,aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R₅ is C1-7 alkanoylamino, aroylamino, C1-7 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-7alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R₅ is C1-7 alkoxycarbonylamino, aryloxycarbonylamino, C1-7alkylcarbamoyloxy, arylcarbamoyloxy, C1-7 alkylsulfonylamino,arylsulfonylamino, C1-7 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-7 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl,

or R₅ is halogen, hydroxy, oxy, oxo, carboxy, cyano, nitro orcarboxamide, R₅ may be further optionally substituted by one or moreR_(e);

R_(e) is C1-7 alkyl, C1-7alkoxyC1-7alkyl, C1-7alkylaminoC1-7alkyl,C1-7alkylthioC1-7alkyl wherein the sulfur atom may be oxidized to asulfoxide or sulfone, C1-7 alkoxy, C3-7 cycloalkyl, aryl,tetrahydronaphthyl, indanyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, thiopyranyl, tetrahydrothiopyranyl,tetrahydropyranyl, tetrahydrofuranyl, furanyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, C1-5 alkanoyl,aroyl, C1-5alkanoyloxy, aryloxy, benzyloxy, C1-5 alkoxycarbonyl,aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

or R_(e) is C1-5 alkanoylamino, aroylamino, C1-5 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-5alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

or R_(e) is C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

or R_(e) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(e) may be further optionally substituted by oneor more R_(f);

R_(f) is methyl, ethyl, t-butyl, tolylsulfonyl, C1-3 alkoxy,cyclopropyl, cyclohexyl, phenyl, naphthyl, phenoxy, benzyloxy, fluoro,chloro, bromo, hydroxy, oxo, carboxy, cyano, nitro or carboxamide;

R₆ is

hydrogen, hydroxy, nitrile or

a C1-6 saturated or unsaturated branched or unbranched carbon chainoptionally partially or fully halogenated wherein one or more C atomsare optionally replaced by O, NH, S(O), S(O)₂ or S and wherein saidchain is optionally independently substituted with 1-2 oxo groups, —NH₂,one or more C1-4 alkyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,benzoxazolyl or quinoxalinyl;

R₁ and R₆ of the formula (Ia) or formula (Ib) form a monocyclic 5, 6 or7 membered aromatic or nonaromatic heterocyclic ring optionallysubstituted by R₇;

or a bicyclic ring having one 5, 6 or 7 membered aromatic or nonaromaticheterocyclic ring fused to a second 5-7 membered aromatic or nonaromaticheterocyclic or carbocyclic ring wherein each ring is optionallyindependently substituted by one or more R₇;

R₇ and R₈ are independently C1-5 alkyl, C3-6 cycloalkyl, aryl, C1-5alkoxy, aryloxy, benzyloxy each of the aforementioned are optionallyhalogenated or R_(x) is halogen, hydroxy, oxo; carboxy, nitrile, nitroor NH₂C(O)—;

m is 0, 1 or 2 and

X is O or S.

In yet another embodiment of the invention, there are provided novelcompounds of the formulas (Ia) and (Ib) as described immediately above,and wherein:

Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepanyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, oxetanyl,octahydro-indolizinyl, octahydroquinolizinyl oraza-bicyclo[3.2.1]octanyl, each ring being optionally substituted withone or more R₅;

R₁ is a bond, C1-5 alkyl, C1-5 alkoxy, C3-6 cycloalkyl, aryloxy, phenyl,benzyl, naphthyl, C1-3alkylsulfonylC1-3alkyl,C3-6cycloalkylsulfonylC1-3alkyl, arylsulfonylC1-3alkyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, isoxazolyl,pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, benzofuranyl,benzthienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl or amino;wherein R₁ is optionally substituted by one or more R₂;

R_(a) is a bond, C1-3 alkyl, cyclopropyl, cyclopentyl, cyclohexyl,phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, C1-3 alkoxy, C1-3alkanoyl, C1-3alkanoyloxy, aryloxy,benzyloxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl, p2 or R_(a) isC1-3 alkanoylamino, aroylamino, C1-3 alkylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-3 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,

or R_(a) is C1-3 alkoxycarbonylamino, aryloxycarbonylamino, C1-3alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino,arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further optionally substituted by oneor more R_(b);

R_(b) is C1-3 alkyl, C3-6 cycloalkyl, aryl, C1-3 alkoxy, aryloxy,benzyloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino;

R₂ is hydrogen or methyl;

R₃ is a bond, hydrogen, C1-5 alkyl, C2-5alkylene, C4-6 cycloalkyl orarylC1-2alkyl wherein R₃ is optionally substituted by one or more R_(c);

R_(c) is C1-4 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, indanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, indolinyl, furanyl, tetrahydrofuranyl, pyranyl,tetrahydropyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, C1-4 alkoxy, phenoxy, naphthyloxy, C1-3alkanoyl, benzoyl, C1-3 alkoxycarbonyl, phenoxycarbonyl, C1-3alkanoyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl or aryl,

or R_(c) is C1-3 alkanoylamino, benzoylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-5 alkyl or aryl, or R_(c) is C1-3 alkoxycarbonylamino,aryloxycarbonylamino, C1-3 alkylcarbamoyloxy, arylcarbamoyloxy, C1-3alkylsulfonylamino, arylsulfonylamino, C1-3 alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-5 alkyl or aryl,

or R_(c) is halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino orguanidino, R_(c) may be further optionally substituted by one or moreR_(d);

R_(d) is C1-3 alkyl, C3-6 cycloalkyl, phenyl, benzyl, C1-3 alkoxy,phenoxy, phenylC1-3alkoxy, benzoyl, halogen, hydroxy, oxo or cyano;

R₄ is hydrogen;

R₅ is a bond, hydrogen, carbonyl, C1-6 alkyl, C1-6alkoxyC1-6alkyl,C1-6alkylaminoC1-6alkyl, C1-6alkylthioC1-6alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-6 alkoxy, phenoxy,naphthyloxy, C3-6 cycloalkyl, phenyl, naphthyl, benzyl, indanyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,furanyl, tetrahydrofuranyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl andbenzoxazolyl, heterocyclyloxy wherein the heterocyclyl moiety isselected from those herein described in this paragraph, C1-3alkanoyl,benzoyl, naphthoyl, C1-4alkanoyloxy, benzyloxy, C1-4 alkoxycarbonyl,arylC1-2alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl whereinthe nitrogen atom may be independently mono or di-substituted by C1-3alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R₅ is C1-4 alkanoylamino, aroylamino, C1-4 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-3alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl orbenzthiazolyl,

or R₅ is C1-4 alkoxycarbonylamino, phenoxycarbonylamino, C1-4alkylcarbamoyloxy, phenylcarbamoyloxy, C1-4 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-4 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

or R₅ is halogen, hydroxy, oxo, carboxy, cyano, nitro or carboxamide, R₅may be further optionally substituted by one or more R_(e);

R_(e) is C1-4 alkyl, C1-4 alkoxy, C3-7 cycloalkyl, phenyl, naphthyl,indanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, tetrahydrothiopyranyl, tetrahydropyranyl,tetrahydrofuranyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-4 alkanoyl, aroyl, C1-4alkanoyloxy, phenoxy, naphthyloxy, benzyloxy,C1-4 alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, or benzthiazolyl,

or R_(e) is C1-4 alkanoylamino, benzoylamino, C1-4 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

or R_(e) is C1-4 alkoxycarbonylamino, phenoxycarbonylamino, C1-4alkylcarbamoyloxy, phenylcarbamoyloxy, C1-4 alkylsulfonylamino,phenylsulfonylamino, C1-4 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

or R_(e) is halogen, hydroxy, oxo, carboxy, cyano, nitro or carboxamide,R_(e) may be further optionally substituted by one or more R_(f);

R_(f) is methyl, ethyl, t-butyl, tolylsulfonyl, methoxy, cyclopropyl,phenyl, phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy, oxo, carboxyor carboxamide.

R₁ and R₆ of the formula (Ia) or Formula (Ib) optionally form amonocyclic 5 or 6 membered aromatic or nonaromatic heterocyclic ringoptionally substituted by R₇;

or a bicyclic ring having one 5, 6 or 7 membered aromatic or nonaromaticheterocyclic ring fused to a second 5-6 membered aromatic or nonaromaticheterocyclic or carbocyclic ring wherein each ring is optionallyindependently substituted by one or more R₇;

R₇ and R₈ are independently C1-4 alkyl, C5-6 cycloalkyl, C1-4 alkoxy,halogen, hydroxy, oxo, carboxy, nitrile, nitro or NH₂C(O)—;

and

X is O.

In yet still another embodiment of the invention, there are providednovel compounds of the formulas (Ia) and (Ib) as described immediatelyabove, and wherein:

Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepanyl,tetrahydropyranyl, oxetanyl or tetrahydrothiopyranyl each ring beingoptionally substituted with one or more R₅;

R₁ is a bond, C1-5 alkyl, C1-5 alkoxy, C3-6 cycloalkyl, aryloxy, phenyl,benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl,quinolinyl, benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl,benzoxazolyl or amino; wherein R₁ is optionally substituted by one ormore R_(a);

R_(a) is a bond, C1-3 alkyl, cyclopropyl, cyclohexyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,thienyl, imidazolyl, C1-3 alkoxy, C1-3alkanoyl, C1-3alkanoyloxy,aryloxy, benzyloxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-3 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl or piperazinyl,

or R_(a) is C1-3 alkanoylamino, aroylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-3alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl orpiperazinyl,

or R_(a) is C1-3 alkoxycarbonylamino, aryloxycarbonylamino, C1-3alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino,arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further optionally substituted by oneor more R_(b);

R_(b) is methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, i-propoxy, phenoxy,benzyloxy, fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy, cyano,nitro or carboxamide;

R₂ is hydrogen;

R₃ is a bond, C1-3 alkyl, C2-4alkylene, C5-6 cycloalkyl, benzyl ornaphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

R_(c) is C1-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, indanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, furanyl, tetrahydropyranyl, thienyl,oxazolyl, thiazolyl, imidazolyl, pyrimidinyl, indolyl, benzofuranyl,benzothienyl, benzthiazolyl, C1-3 alkoxy, phenoxy, naphthyloxy, C1-2alkanoyl, benzoyl, C1-2 alkoxycarbonyl, phenoxycarbonyl,C1-2alkanoyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or aryl,

or R_(c) is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl or aryl,

or R_(c) is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, arylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl or phenyl,

or R_(c) is halogen, hydroxy, oxo, carboxy or cyano, R_(c) may befurther optionally substituted by one or more R_(d);

R_(d) is methyl, cyclopropyl, cyclohexyl, phenyl, benzyl, methoxy,phenoxy, benzyloxy, benzoyl, fluoro, chloro, oxo or cyano;

R₅ is a bond, hydrogen, carbonyl, C1-5 alkyl, C1-5alkoxyC1-5alkyl,C1-5alkylaminoC1-5alkyl, C1-5alkylthioC1-5alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-5 alkoxy, phenoxy, C3-6cycloalkyl, phenyl, naphthyl, benzyl, indanyl, heterocyclyl selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl and benzthiazolyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-3alkanoyl, benzoyl, naphthoyl,C1-3alkanoyloxy, benzyloxy, C1-3 alkoxycarbonyl, benzyloxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R₅ is C1-3 alkanoylamino, aroylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzofuranyl,benzothienyl, benzimidazolyl or benzthiazolyl,

or R₅ is C1-3 alkoxycarbonylamino, phenoxycarbonylamino, C1-3alkylcarbamoyloxy, phenylcarbamoyloxy, C1-3 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

or R₅ is halogen, hydroxy, oxo, carboxy, cyano or carboxamide, R₅ may befurther optionally substituted by one or more R_(e);

R_(e) is C1-3 alkyl, C1-3 alkoxy, C3-7 cycloalkyl, phenyl, naphthyl,indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,C1-3 alkanoyl, aroyl, C1-3alkanoyloxy, phenoxy, benzyloxy, C1-3alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl orbenzthiazolyl,

or R_(e) is C1-3 alkanoylamino, benzoylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolylor benzthiazolyl,

or R_(e) is C1-3 alkoxycarbonylamino, phenoxycarbonylamino, C1-3alkylcarbamoyloxy, phenylcarbamoyloxy, C1-3 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,benzimidazolyl or benzthiazolyl,

or R_(e) is halogen, hydroxy, oxo, carboxy, cyano or carboxamide, R_(e)may be further optionally substituted by one or more R_(f);

and

R_(f) is methyl, phenyl, tolylsulfonyl, methoxy, phenoxy, benzyloxy,fluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide;

R₁ and R₆ of the formula (Ia) or Formula (Ib) form a bicyclic ringhaving one 5 or 6 membered aromatic or nonaromatic heterocyclic ringfused to a second 5-6 membered heteroaryl, heterocycle or phenyl ring;

wherein each ring is optionally independently substituted by one or twoR₇.

In yet a further embodiment of the invention, there are provided novelcompounds of the formulas (Ia) and (Ib) as described immediately above,and wherein:

Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl ortetrahydropyranyl each ring being substituted with one or more R₅;

R₁ is a bond, methyl, ethyl, i-propyl, methoxy, ethoxy, cyclopropyl,cyclopentyl, cyclohexyl, phenoxy, phenyl, benzyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, pyrazinyl or amino;wherein R₁ is optionally substituted by one or more R_(a);

R_(a) is a bond, methyl, ethyl, cyclopropyl, phenyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, thienyl,imidazolyl, methoxy, acetyl, acetoxy, phenoxy, benzyloxy,methoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl,

or R_(a) is acetylamino, benzoylamino, methylthio, phenylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by methyl,ethyl or phenyl,

or R_(a) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

or R_(a) is fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy, cyano,nitro or carboxamide, R_(a) may be further optionally substituted by oneor more R_(b);

R_(b) is methyl, cyclopropyl, phenyl, methoxy, phenoxy, benzyloxy,fluoro, chloro, hydroxy, oxo, carboxy or carboxamide;

R₃ is a bond, C1-3 alkyl, C2-4alkylene, C5-6 cycloalkyl, benzyl ornaphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

R_(c) is methyl, ethyl, n-propyl, i-propyl, C5-6 cycloalkyl, indanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, thienyl, oxazolyl, thiazolyl, indolyl,benzofuranyl, benzothienyl, benzthiazolyl, methoxy, ethoxy, phenoxy,acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by methyl, ethyl or aryl,

or R_(c) is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, phenylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by methyl, ethylor aryl,

or R_(c) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl, ethyl or phenyl,

or R_(c) is fluoro, chloro or oxo, R_(c) may be further optionallysubstituted by one or more R_(d);

R_(d) is methyl, cyclopropyl, phenyl, methoxy, fluoro, chloro or oxo;

R₅ is a bond, hydrogen, carbonyl, C1-4 alkyl, C1-4alkoxyC1-4alkyl,C1-4alkylaminoC1-4alkyl, C1-4alkylthioC1-4alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-4 alkoxy,phenoxy,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, benzyl, indanyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl and benzthiazolyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-2alkanoyl, benzoyl, naphthoyl,C1-2alkanoyloxy, benzyloxy, C1-2 alkoxycarbonyl, benzyloxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R₅ is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolylor benzthiazolyl,

or R₅ is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, phenylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R₅ is fluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide, R₅may be further optionally substituted by one or more R_(e);

R_(e) is C1-3 alkyl, C1-2 alkoxy, C3-6 cycloalkyl, phenyl, naphthyl,indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,C1-2 alkanoyl, aroyl, C1-2alkanoyloxy, phenoxy, benzyloxy, C1-2alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-2 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R_(e) is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R_(e) is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, phenylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-2 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R_(e) is fluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide,R_(e) may be further optionally substituted by one or more R_(f);

R_(f) is methyl, phenyl, tolylsulfonyl, methoxy, phenoxy, benzyloxy,fluoro, chloro, hydroxy, oxo, carboxy or carboxamide and

R₁ and R₆ of the formula (Ia) or Formula (Ib) form a bicyclic ringhaving one 5-6 membered aromatic or nonaromatic heterocyclic ring fusedto a phenyl ring;

wherein each ring is optionally independently substituted by one or twoR₇.

In yet still a further embodiment of the invention, there are providednovel compounds of the formula (Ia) or formula (Ib) as describedimmediately above, and wherein:

Het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl, azetidin-3-yl,azepan-3-yl, azepan-4-yl or tetrahydropyran-4-yl, each ring beingoptionally substituted with one or more R₅;

R₁ is a bond, methyl, ethyl, i-propyl, methoxy, cyclopropyl, cyclohexyl,phenoxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, thiazolyl,imidazolyl, pyridinyl, pyrazinyl or amino; wherein R₁ is optionallysubstituted by one or more R_(a);

R_(a) is methyl, phenyl, thienyl, methoxy, acetyl, acetoxy, phenoxy,benzyloxy, methoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogenatom may be independently mono or di-substituted by methyl or phenyl,

or R_(a) is acetylamino, methylthio, phenylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl or phenyl,

or R_(a) is methoxycarbonylamino, methylcarbamoyloxy,phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

or R_(a) is fluoro, chloro, hydroxy, oxo, carboxy, cyano or carboxamide;

R₃ is a bond, methyl, ethyl, n-propyl, propenyl, butenyl, i-butenyl,cyclohexyl, benzyl or naphthylmethyl wherein R₃ is optionallysubstituted by one or more R_(c);

R_(c) is methyl, ethyl, n-propyl, i-propyl, cyclohexyl, cyclopentyl,indanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl,bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl,cubanyl, 1,2,3,4-tetrahydronaphthyl, methoxy, phenoxy, acetyl, benzoyl,methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy, methylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, fluoro, chloro or oxo;

R₅ is a bond, hydrogen, carbonyl, C1-4 alkyl, C1-2alkoxyC1-2alkyl,C1-2alkylaminoC1-2alkyl, C1-2alkylthioC1-2alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-2 alkoxy, phenoxy,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl,pyridinyl, and pyrimidinyl, heterocyclyloxy wherein the heterocyclylmoiety is selected from those herein described in this paragraph,acetyl, benzoyl, acetyloxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl,benzyloxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom maybe independently mono or di-substituted by methyl, ethyl or phenyl,

or R₅ is acetylamino, benzoylamino, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl orphenyl,

or R₅ is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

or R₅ is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R₅ may befurther optionally substituted by one or more R_(e);

R_(e) is methyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl,phenyl, naphthyl, indanyl, piperidinyl, morpholinyl, indolyl, thienyl,pyridinyl, acetyl, benzoyl, acetyloxy, phenoxy, benzyloxy,methoxycarbonyl, ethoxycarbonyl, carbamoyl wherein the nitrogen atom maybe independently mono or di-substituted by methyl, ethyl or phenyl,

or R_(e) is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, phenylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by methyl, ethylor phenyl,

or R_(e) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

or R_(e) is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R_(e)may be further optionally substituted by one or more R_(f);

and

R_(f) is methyl, phenyl, tolylsulfonyl, phenoxy, benzyloxy, fluoro,chloro or oxo;

R₁ and R₆ of the formula (Ia) or Formula (Ib) form the bicyclic ring

 wherein W is —S(O)_(n)—, —O—C(O)— or —N—C(O)—, n is 0, 1 or 2 andwherein each ring is optionally independently substituted by one or twoR₇.

In a further embodiment of the invention, there are provided novelcompounds of the formulas (Ia) and (Ib) as described immediately above,and wherein:

Het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl, azetidin-3-yl ortetrahydropyran-4-yl, each ring being substituted with one or more R₅;

R₁ is i-propyl, benzyloxy, cyclohexyl, phenyl, 4-(acetylamino)-phenyl,4-(methanesulfonylamino)-phenyl, 4-methoxyphenyl, 3-phenoxyphenyl,4-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl,naphthyl, thienylmethyl, piperidinyl, morpholinyl, pyrrolidinyl,piperazinyl, furanyl, thienyl, 5-chlorothienyl, pyridin-4-yl, pyrazinyl,methylamino, ethylamino, dimethylamino or diethylamino;

R₃ is ethyl, n-propyl,propenyl, butenyl, i-butenyl, benzyl ornaphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

R_(c) is methyl, cyclohexyl, cyclopentyl, indanyl,1,2,3,4-tetrahydronaphthyl, methoxy, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, fluoro or chloro;

R₅ is a bond, carbonyl, methyl, ethyl, n-propyl, n-butyl, t-butyl,i-propyl, i-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl,piperidinyl, tetrahydropyranyl, pyrimidinyl, acetyl, benzoyl,ethoxycarbonyl, benzyloxycarbonyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxo or carboxy,R₅ may be further optionally substituted by one or more R_(e);

R_(e) is methyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl,indanyl, thienyl, 5-methylthienyl, methoxy, phenoxy, benzyloxy,piperidinyl, pyridinyl, indolyl, 1-(tolyl-sulfonyl)-indolyl, carbamoylwherein the nitrogen atom may be independently mono or di-substituted bymethyl, phenyl or benzyl,

or R_(e) is hydroxy, fluoro, chloro, oxo, dimethylamino ortrifluoromethyl;

and

n is 2.

In another embodiment of the invention, there are provided novelcompounds of the formulas (Ia) and (Ib) as described for the broadestgeneric aspect above and wherein:

R₁ and R₆ remain acyclic,

Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepanyl,tetrahydropyranyl, oxetanyl or tetrahydrothiopyranyl each ring beingoptionally substituted with one or more R₅;

R₁ is a bond, C1-5 alkyl, C1-5 alkoxy, C3-6 cycloalkyl, aryloxy, phenyl,benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl,quinolinyl, benzoffiranyl, benzthienyl, benzimidazolyl, benzthiazolyl,benzoxazolyl or amino; wherein R₁ is optionally substituted by one ormore R_(a);

R_(a) is a bond, C1-3 alkyl, cyclopropyl, cyclohexyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,thienyl, imidazolyl, C1-3 alkoxy, C1-3alkanoyl, C1-3alkanoyloxy,aryloxy, benzyloxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-3 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl or piperazinyl,

or R_(a) is C1-3 alkanoylamino, aroylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-3alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl orpiperazinyl,

or R_(a) is C1-3 alkoxycarbonylamino, aryloxycarbonylamino, C1-3alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino,arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further optionally substituted by oneor more R_(b);

R_(b) is methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, i-propoxy, phenoxy,benzyloxy, fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy, cyano,nitro or carboxamide;

R₂ is hydrogen; Z

R₃ is a bond, C1-3 alkyl, C2-4alkylene, C5-6 cycloalkyl, benzyl ornaphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

R_(c) is C1-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, indanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1. ]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, furanyl, tetrahydropyranyl, thienyl,oxazolyl, thiazolyl, imidazolyl, pyrimidinyl, indolyl, benzofuranyl,benzothienyl, benzthiazolyl, C1-3 alkoxy, phenoxy, naphthyloxy, C1-2alkanoyl, benzoyl, C1-2 alkoxycarbonyl, phenoxycarbonyl,C1-2alkanoyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or aryl, or R_(c) isC1-2 alkanoylamino, benzoylamino, C1-2 alkylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-3 alkyl or aryl,

or R_(c) is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, arylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl or phenyl,

or R_(c) is halogen, hydroxy, oxo, carboxy or cyano, R_(c) may befurther optionally substituted by one or more R_(d);

R_(d) is methyl, cyclopropyl, cyclohexyl, phenyl, benzyl, methoxy,phenoxy, benzyloxy, benzoyl, fluoro, chloro, oxo or cyano;

R₄ is hydrogen;

R₅ is a bond, hydrogen, carbonyl, C1-5 alkyl, C1-5alkoxyC1-5alkyl,C1-5alkylaminoC1-5alkyl, C1-5alkylthioC1-5alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-5 alkoxy, phenoxy, C3-6cycloalkyl, phenyl, naphthyl, benzyl, indanyl, heterocyclyl selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl and benzthiazolyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-3alkanoyl, benzoyl, naphthoyl,C1-3alkanoyloxy, benzyloxy, C1-3 alkoxycarbonyl, benzyloxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R₅ is C1-3 alkanoylamino, aroylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzofuranyl,benzothienyl, benzimidazolyl or benzthiazolyl,

or R₅ is C1-3 alkoxycarbonylamino, phenoxycarbonylamino, C1-3alkylcarbamoyloxy, phenylcarbamoyloxy, C1-3 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

or R₅ is halogen, hydroxy, oxo, carboxy, cyano or carboxamide, R₅ may befurther optionally substituted by one or more R_(e);

R_(e) is C1-3 alkyl, C1-3 alkoxy, C3-7 cycloalkyl, phenyl, naphthyl,indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,C1-3 alkanoyl, aroyl, C1-3alkanoyloxy, phenoxy, benzyloxy, C1-3alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl orbenzthiazolyl,

or R_(e) is C1-3 alkanoylamino, benzoylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolylor benzthiazolyl,

or R_(e) is C1-3 alkoxycarbonylamino, phenoxycarbonylamino, C1-3alkylcarbamoyloxy, phenylcarbamoyloxy, C1-3 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,benzimidazolyl or benzthiazolyl,

or R_(e) is halogen, hydroxy, oxo, carboxy, cyano or carboxamide, R_(e)may be further optionally substituted by one or more R_(f);

R_(f) is methyl, phenyl, tolylsulfonyl, methoxy, phenoxy, benzyloxy,fluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide;

R₆ is

hydroxy, nitrile or

a C1-5 saturated or unsaturated branched or unbranched carbon chainoptionally partially or fully halogenated wherein one or more C atomsare optionally replaced by O, NH, or S(O)₂ and wherein said chain isoptionally independently substituted with 1-2 oxo groups, —NH₂, one ormore C1-4 alkyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,benzoxazolyl or quinoxalinyl;

and

X is O.

In another embodiment of the invention, there are provided novelcompounds of the formula (Ia) and (Ib) as described immediately above,and wherein:

R₁ is a bond, methyl, ethyl, i-propyl, methoxy, ethoxy, cyclopropyl,cyclopentyl, cyclohexyl, phenoxy, phenyl, benzyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, pyrazinyl or amino;wherein R₁ is optionally substituted by one or more R_(a);

R_(a) is a bond, methyl, ethyl, cyclopropyl, phenyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, thienyl,imidazolyl, methoxy, acetyl, acetoxy, phenoxy, benzyloxy,methoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl,

or R_(a) is acetylamino, benzoylamino, methylthio, phenylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by methyl,ethyl or phenyl,

or R_(a) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

or R_(a) is fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy, cyano,nitro or carboxamide, R_(a) may be further optionally substituted by oneor more R_(b);

R_(b) is methyl, cyclopropyl, phenyl, methoxy, phenoxy, benzyloxy,fluoro, chloro, hydroxy, oxo, carboxy or carboxamide;

R₃ is a bond, C1-3 alkyl, C2-4alkylene, C5-6 cycloalkyl, benzyl ornaphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

R_(c) is methyl, ethyl, n-propyl, i-propyl, C5-6 cycloalkyl, indanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, thienyl, oxazolyl, thiazolyl, indolyl,benzofuranyl, benzothienyl, benzthiazolyl, methoxy, ethoxy, phenoxy,acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by methyl, ethyl or aryl,

or R_(c) is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, phenylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by methyl, ethylor aryl,

or R_(c) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl, ethyl or phenyl,

or R_(c) is fluoro, chloro or oxo, R_(c) may be further optionallysubstituted by one or more R_(d);

R_(d) is methyl, cyclopropyl, phenyl, methoxy, fluoro, chloro or oxo;

R₅ is a bond, hydrogen, carbonyl, C1-4 alkyl, C1-4alkoxyC1-4alkyl,C1-4alkylaminoC1-4alkyl, C1-4alkylthioC1-4alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-4 alkoxy,phenoxy,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, benzyl, indanyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl and benzthiazolyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-2alkanoyl, benzoyl, naphthoyl,C1-2alkanoyloxy, benzyloxy, C1-2 alkoxycarbonyl, benzyloxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R₅ is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolylor benzthiazolyl,

or R₅ is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, phenylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R₅ is fluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide, R₅may be further optionally substituted by one or more R_(e);

R_(e) is C1-3 alkyl, C1-2 alkoxy, C3-6 cycloalkyl, phenyl, naphthyl,indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,C1-2 alkanoyl, aroyl, C1-2alkanoyloxy, phenoxy, benzyloxy, C1-2alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-2 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R_(e) is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R_(e) is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, phenylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-2 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

or R_(e) is fluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide,R_(e) may be further optionally substituted by one or more R_(f);

R_(f) is methyl, phenyl, tolylsulfonyl, methoxy, phenoxy, benzyloxy,fluoro, chloro, hydroxy, oxo, carboxy or carboxamide and

R₆ is

nitrile or

a C1-5 saturated or unsaturated branched or unbranched carbon chainoptionally partially or fully halogenated wherein one or more C atomsare optionally replaced by O, NH, or S(O)₂ and wherein said chain isoptionally independently substituted with oxo, —NH₂, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, pyridinyl, pyrimidinyl orpyrazinyl.

In yet another embodiment of the invention, there are provided novelcompounds of the formula (Ia) or formula (Ib) as described immediatelyabove, and wherein:

Het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl, azetidin-3-yl,azepan-3-yl, azepan-4-yl or tetrahydropyran-4-yl, each ring beingoptionally substituted with one or more R₅;

R₁ is a bond, methyl, ethyl, i-propyl, methoxy, cyclopropyl, cyclohexyl,phenoxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, thiazolyl,imidazolyl, pyridinyl, pyrazinyl or amino; wherein R₁ is optionallysubstituted by one or more R_(a);

R_(a) is methyl, phenyl, thienyl, methoxy, acetyl, acetoxy, phenoxy,benzyloxy, methoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogenatom may be independently mono or di-substituted by methyl or phenyl,

or R_(a) is acetylamino, methylthio, phenylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl or phenyl,

or R_(a) is methoxycarbonylamino, methylcarbamoyloxy,phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

or R_(a) is fluoro, chloro, hydroxy, oxo, carboxy, cyano or carboxamide;

R₃ is a bond, methyl, ethyl, n-propyl, propenyl, butenyl, i-butenyl,cyclohexyl, benzyl or naphthylmethyl wherein R₃ is optionallysubstituted by one or more R_(a);

R_(a) is methyl, ethyl, n-propyl, i-propyl, cyclohexyl, cyclopentyl,indanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl,bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl,cubanyl, 1,2,3,4-tetrahydronaphthyl, methoxy, phenoxy, acetyl, benzoyl,methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy, methylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, fluoro, chloro or oxo;

and

wherein the configuration at the stereocenter defined by R₂ and R₃ whenthey are different and the carbon they are attached to is defined as L;and

R₅ is a bond, hydrogen, carbonyl, C1-4 alkyl, C1-2alkoxyC1-2alkyl,C1-2alkylaminoC1-2alkyl, C1-2alkylthioC1-2alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-2 alkoxy, phenoxy,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl,pyridinyl, and pyrimidinyl, heterocyclyloxy wherein the heterocyclylmoiety is selected from those herein described in this paragraph,acetyl, benzoyl, acetyloxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl,benzyloxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom maybe independently mono or di-substituted by methyl, ethyl or phenyl,

or R₅ is acetylamino, benzoylamino, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl orphenyl,

or R₅ is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

or R₅ is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R₅ may befurther optionally substituted by one or more R_(e);

R_(e) is methyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl,phenyl, naphthyl, indanyl, piperidinyl, morpholinyl, indolyl, thienyl,pyridinyl, acetyl, benzoyl, acetyloxy, phenoxy, benzyloxy,methoxycarbonyl, ethoxycarbonyl, carbamoyl wherein the nitrogen atom maybe independently mono or di-substituted by methyl, ethyl or phenyl,

or R_(e) is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, phenylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by methyl, ethylor phenyl,

or R_(e) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

or R_(e) is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R_(e)may be further optionally substituted by one or more R_(f);

R_(f) is methyl, phenyl, tolylsulfonyl, phenoxy, benzyloxy, fluoro,chloro or oxo;

R₆ is

nitrile or

a C1-5 saturated or unsaturated branched or unbranched carbon chainoptionally partially or fully halogenated wherein one or more C atomsare optionally replaced by O, NH, or S(O)₂ and wherein said chain isoptionally independently substituted with oxo, —NH₂, morpholinyl orpiperazinyl.

In yet still another embodiment of the invention, there are providednovel compounds of the formulas (Ia) and (Ib) as described immediatelyabove, and wherein:

Het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl, azetidin-3-yl ortetrahydropyran-4-yl, each ring being substituted with one or more R₅;

R₁ is i-propyl, benzyloxy, cyclohexyl, phenyl, 4-(acetylamino)-phenyl,4-(methanesulfonylamino)-phenyl, 4-methoxyphenyl, 3-phenoxyphenyl,4-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl,naphthyl, thienylmethyl, piperidinyl, morpholinyl, pyrrolidinyl,piperazinyl, furanyl, thienyl, 5-chlorothienyl, pyridin-4-yl, pyrazinyl,methylamino, ethylamino, dimethylamino or diethylamino;

R₃ is ethyl, n-propyl, propenyl, butenyl, i-butenyl, benzyl ornaphthylmethyl wherein R₃ is optionally substituted by one or moreR_(e);

R_(c) is methyl, cyclohexyl, cyclopentyl, indanyl,1,2,3,4-tetrahydronaphthyl, methoxy, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, fluoro or chloro;

R₅ is bond, carbonyl, methyl, ethyl, n-propyl, n-butyl, t-butyl,i-propyl, i-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl,piperidinyl, tetrahydropyranyl, pyrimidinyl, acetyl, benzoyl,ethoxycarbonyl, benzyloxycarbonyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxo or carboxy,R₅ may be further optionally substituted by one or more R_(e);

R_(e) is methyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl,indanyl, thienyl, 5-methylthienyl, methoxy, phenoxy, benzyloxy,piperidinyl, pyridinyl, indolyl, 1-(tolyl-sulfonyl)-indolyl, carbamoylwherein the nitrogen atom may be independently mono or di-substituted bymethyl, phenyl or benzyl, or R_(e) is hydroxy, fluoro, chloro, oxo,dimethylamino or trifluoromethyl;

and

R₆ is acetyl, C1-3alkylaminocarbonyl or C1-3alkoxycarbonyl.

In yet a further embodiment of the invention, there are provided novelcompounds of the formulas (Ia) and (Ib) as described immediately above,and wherein:

Het is piperidin-4-yl or pyrrolidin-3-yl;

R₁ is morpholin-4-yl, p-fluorophenyl or p-methoxyphenyl;

R₅ is methyl, propyl, n-pentyl or cyclohexyl

and

R₆ is acetyl, ethylaminocarbonyl or ethoxycarbonyl.

The activity of particular compounds disclosed herein against cathepsinK may be determined without undue experimentation by one of ordinaryskill in the art in view of the art, the guidance provided throughoutthis specification and by the screens described in the section entitled“Assessment of Biological Properties.”

The following subgeneric aspect of the compounds of the formulas (Ia)and (Ib) is postulated to possess Cathepsin K activity:

The broadest embodiment of the formula (Ia) and (Ib) as describedhereinabove and wherein

Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepanyl,tetrahydropyranyl, oxetanyl or tetrahydrothiopyranyl each ring beingoptionally substituted with one or more R₅;

R₁ is a bond, C1-4 alkyl, C1-4 alkoxy, cyclopropyl, cyclohexyl, phenoxy,naphthyloxy, phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,indolyl, quinolinyl, benzofuranyl, benzthienyl, benzimidazolyl,benzithiazolyl, benzoxazolyl or amino; wherein R₁ is optionallysubstituted by one or more R_(a);

R_(a) is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclohexyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, thienyl, imidazolyl, methoxy, ethoxy, acetyl, acetoxy,phenoxy, naphthyloxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl,phenoxycarbonyl, naphthyloxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

or R_(a) is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ethylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

or R_(a) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, C1-2 alkylcarbamoyloxy, phenylcarbamoyloxy,naphthylcarbamoyloxy, C1-2 alkylsulfonylamino, phenylsulfonylamino,naphthylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl,naphthylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl, phenyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,

or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further optionally substituted by oneor more R_(b);

R_(b) is methyl, ethyl, cyclopropyl, cyclohexyl, phenyl, methoxy,ethoxy, phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy, oxo,carboxy, cyano, nitro or carboxamide;

R₂ is hydrogen or methyl;

R₃ is a bond, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,n-pentyl, propenyl, i-butenyl, cyclohexyl, benzyl or naphthylmethylwherein R₃ is optionally substituted by one or more R_(a);

R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl, naphthyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl, furanyl,tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyrimidinyl, methoxy, ethoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl,phenoxycarbonyl, acetoxy, benzoyloxy, carbamoyl wherein the nitrogenatom may be independently mono or di-substituted by methyl or phenyl,

or R_(c) is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, phenylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by methyl orphenyl,

or R_(c) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

or R_(c) is chloro, fluoro, hydroxy, oxo, carboxy or cyano;

R₂ and R₃ together with the carbon they are attached optionally form aring selected from cyclopentyl, cyclohexyl, cycloheptyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl ortetrahydrothiophenyl;

R₄ is hydrogen;

R₅ is a bond, hydrogen, carbonyl, C1-5 alkyl, C1-5alkoxyC1-5alkyl,C1-5alkylaminoC1-5alkyl, C1-5alkylthioC1-5alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-5 alkoxy, phenoxy,naphthyloxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,tetrahydropyranyl, pyridinyl, and pyrimidinyl, heterocyclyloxy whereinthe heterocyclyl moiety is selected from those herein described in thisparagraph, acetyl, benzoyl, acetoxy, benzyloxy, methoxycarbonyl,ethoxycarbonyl, benzyloxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl,

or R₅ is acetylamino, benzoylamino, phenylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl orphenyl,

or R₅ is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,phenylsulfonylamino, phenylaminosulfonyl, amino wherein the nitrogenatom may be independently mono or di-substituted by methyl, ethyl orphenyl,

or R₅ fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R₅ may befurther optionally substituted by one or more R_(e);

R_(e) is methyl ethyl, methoxy, ethoxy, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, naphthyl, indanyl, piperidinyl, morpholinyl,indolyl, thienyl, pyridinyl, methoxy, ethoxy, acetyl, benzoyl,acetyloxy, phenoxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by methyl, ethyl or phenyl,

or R_(e) is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, phenylthio methylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl or phenyl,

or R_(e) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

or R_(e) is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R_(e)may be further optionally substituted by one or more R_(f);

R_(f) is methyl, phenyl, tolylsulfonyl, phenoxy, benzyloxy, fluoro,chloro or oxo.

Preferred cathepsin K inhibitors are those as described immediatelyabove and wherein:

R₁ is a bond, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy,benzyloxy, cyclopropyl, cyclohexyl, phenoxy, naphthyloxy, phenyl,benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl,quinolinyl, benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl,benzoxazolyl or amino; wherein R₁ is optionally substituted by one ormore R_(a);

R_(a) is methyl, cyclopropyl, phenyl, halogen, hydroxy, oxo, carboxy,cyano, nitro or carboxamide;

R₃ is bond, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,n-pentyl, propenyl, i-butenyl, benzyl or naphthylmethyl wherein R₃ isoptionally substituted by one or more R_(c);

R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl, furanyl,tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, methoxy, phenoxy,acetyl, benzoyl, methoxycarbonyl, carbamoyl wherein the nitrogen atommay be independently mono or di-substituted by methyl or phenyl,

or R_(c) is acetylamino, benzoylamino, methylthio, methoxycarbonylamino,methylcarbamoyloxy, methylsulfonylamino, methylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl,

or R_(c) is fluoro or oxo;

R₂ and R₃ together with the carbon they are attached optionally form aring selected from cyclopentyl, cyclohexyl, cycloheptyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,pyrrolidinyl or piperidinyl;

R₅ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, 2-pentyl, 3-pentyl,phenethyl, phenpropyl, 2,2-dimethylpropyl, t-butyl, i-propyl, i-butyl,cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, 2-methylbenzyl,3-methylbenzyl, 4-methylbenzyl, 2,6-dimethylbenzyl, 2,5-dimethylbenzyl,2,4-dimethylbenzyl, 2,3-dimethylbenzyl, 3,4-dimethylbenzyl,3,5-dimethylbenzyl, 2,4,6-trimethylbenzyl, 2-methoxybenzyl,3-methoxybenzyl, 4-methoxybenzyl, 2-phenoxybenzyl, 3-phenoxybenzyl,4-phenoxybenzyl, 2-benzyloxybenzyl, 3-benzyloxybenzyl,4-benzyloxybenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,2,6-difluorobenzyl, 2,5-difluorobenzyl, 2,4-difluorobenzyl,2,3-difluorobenzyl, 3,4-difluorobenzyl, 3,5-difluorobenzyl,2,4,6-triflurobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, naphthylmethyl, indanylmethyl, pyridinylmethyl,indolylmethyl, thienylmethyl, 5-methylthienylmethyl, piperidinyl,piperidinylcarbonyl, pyridinylcarbonyl, tetrahydropyranyl, pyrimidinyl,acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl,methylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxo or carboxy.

Most referred cathepsin K inhibitors are those as described immediatelyabove and wherein:

R₁ is ethoxy, benzyloxy, cyclohexyl, phenoxy, naphthyloxy, phenyl,benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl,benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl, benzoxazolylor amino; wherein R₁ is optionally substituted by one or more R_(a);

R_(a) is methyl, phenyl, fluoro, chloro, hydroxy, oxo, carboxy orcarboxamide;

R₃ is a bond, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,n-pentyl, propenyl, i-butenyl or benzyl wherein R₃ is optionallysubstituted by one or more R_(c);

R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl, furanyl,tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, methoxy, phenoxy,acetyl, benzoyl, methoxycarbonyl, acetylamino, methylthio,methylsulfonylamino or fluoro;

R₂ and R₃ together with the carbon they are attached optionally form aring selected from cyclopentyl, cyclohexyl, cycloheptyl,tetrahydropyranyl, tetrahydrothiopyranyl or tetrahydrofuranyl;

R₅ is ethyl, ethyl, n-propyl, n-butyl, phenethyl, phenpropyl, t-butyl,i-propyl, i-butyl, cyclopropyl, cyclohexyl, cyclopropylmethyl,cyclohexylmethyl, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl,4-methoxybenzyl 4-fluorobenzyl, 3,5-difluorobenzyl,4-trifluoromethylbenzyl, naphthylmethyl, pyridinylmethyl, indolylmethyl,thienylmethyl, acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl,t-butoxycarbonyl, phenylcarbamoyl, phenylsulfonylamino or fluoro.

Most referred cathepsin K inhibitors are those as described immediatelyabove and wherein:

Het is pyrrolidinyl, piperidinyl or tetrahydropyranyl;

R₁ is benzyloxy, phenoxy, naphthyloxy, phenyl, naphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyridinyl,indolyl, quinolinyl, benzofuranyl, benzthienyl, benzimidazolyl,benzthiazolyl, benzoxazolyl or phenylamino;

R₃ is -propyl, i-butyl, propenyl, i-butenyl or 2,2-dimethylpropyl;

R₂ and R₃ together with the carbon they are attached optionally form aring selected from cyclopentyl, cyclohexyl, or cycloheptyl;

R₅ is methyl, ethyl, n-propyl, phenethyl, t-butyl, i-propyl, i-butyl,cyclohexyl, cyclohexylmethyl, benzyl, 4-fluorobenzyl, naphthylmethyl,acetyl, benzoyl or benzyloxycarbonyl.

The following are representative compounds of the invention whichpossess desirable inhibition activity of Cathepsin S in a cell basedassay as described in Riese, R. J. et al., Immunity, 1996, 4, 357-366,incorporated herein by reference.

′2-[(Acetylimino-phenyl-methyl)-amino]-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide;

′({1-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester;

′2-(N-Cyano-benzimidoyl-amino)-N-(4-cyano-1-methyl-piperidine-4-yl)-3-cyclohexyl-propionamide;

′N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-phenyl-methyl)-amino]-propionamide;

′N-[4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide;

′N-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide;

N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide;

N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide;

′2-(1,1-Dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide

and the pharmaceutically acceptable derivatives thereof.

Another embodiment of the invention provides for the following compoundswhich have demonstrated potent inhibition of Cathepsin S in a cell basedassay at concentrations of 50 nM or less.

{[1-4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester;

N-(4-Cyano-methyl-piperidin-4-yl)-3-cyclohexyl-2-(3-oxo-3H-isoindol-1-ylamino)-propionamide;

4,4-Dimethyl-2-(3-oxo-3H-isoindol-1-ylamino)-pentanoicacid-(4-cyano-1-propyl-piperidin-4-yl)-amide;

N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylaminio)-propionamide;

{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-piperidin-1-yl-methyl}-carbamicacid ethyl ester;

′2-[(Acetylimino-phenyl-methyl)-amino]-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide;

′{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylen}-carbamicacid ethyl ester;

′2-[(Acetylimino-phenyl-methyl)-amino]-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide;

′({1-[-3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester;

′N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-phenyl-methyl)-amino]-propionamide;

′N-[4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide;

N-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide;

N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide;

N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamideand

′2-(1,1-Dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide.

Any compounds of this invention containing one or more asymmetric carbonatoms may occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. All such isomericforms of these compounds are expressly included in the presentinvention. Each stereogenic carbon may be in the R or S configurationunless otherwise specified, or a combination of configurations.

Some of the compounds of formulas (I), (II), (Ia) and (Ib) can exist inmore than one tautomeric form. The invention includes all suchtautomers.

It shall be understood by one of ordinary skill in the art that allcompounds of the invention are those which are chemically stable.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I), (II), (Ia) and (Ib). A “pharmaceuticallyacceptable derivative” refers to any pharmaceutically acceptable acid,salt or ester of a compound of this invention, or any other compoundwhich, upon administration to a patient, is capable of providing(directly or indirectly) a compound of this invention, apharmacologically active metabolite or pharmacologically active residuethereof.

In addition, the compounds of this invention include prodrugs ofcompounds of the formulas (I), (II), (Ia) and (Ib). Prodrugs includethose compounds that, upon simple transformation, are modified toproduce the compounds of the invention. Simple chemical transformationsinclude hydrolysis, oxidation and reduction which occur enzymatically,metabolically or otherwise. Specifically, when a prodrug of thisinvention is administered to a patient, the prodrug may be transformedinto a compound of formula (I), (Ia) and (Ib), thereby imparting thedesired pharmacological effect.

In order that the invention herein described may be more fullyunderstood, the following detailed description is set forth. As usedherein, the following abbreviations are used:

BOC or t-BOC is tertiary-butoxycarbonyl;

t-Bu is tertiary-butyl;

DMF is dimethylformamide;

EtOAc is ethyl acetate;

THF is tetrahydrofuran;

Ar is Ergon;

EDC is 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride and

HOBT is 1-hydroxybenzotriazole.

Also, as used herein, each of the following terms, used alone or inconjunction with other terms, are defined as follows (except where notedto the contrary):

The term “alkyl” refers to a saturated aliphatic radical containing fromone to ten carbon atoms or a mono- or polyunsaturated aliphatichydrocarbon radical containing from two to twelve carbon atoms. Themono- or polyunsaturated aliphatic hydrocarbon radical containing atleast one double or triple bond, respectively. “Alkyl” refers to bothbranched and unbranched alkyl groups. Examples of “alkyl” include alkylgroups which are straight chain alkyl groups containing from one toeight carbon atoms and branched alkyl groups containing from three toeight carbon atoms. Other examples include lower alkyl groups which arestraight chain alkyl groups containing from one to six carbon atoms andbranched alkyl groups containing from three to six carbon atoms. Itshould be understood that any combination term using an “alk” or “alkyl”prefix refers to analogs according to the above definition of “alkyl”.For example, terms such as “alkoxy”, “alkythio” refer to alkyl groupslinked to a second group via an oxygen or sulfur atom. “Alkanoyl” refersto an alkyl group linked to a carbonyl group (C═O). Each alkyl or alkylanalog described herein shall be understood to be optionally partiallyor fully halogenated.

The term “cycloalkyl” refers to the cyclic analog of an alkyl group, asdefined above. Examples of cycloalkyl groups are saturated orunsaturated nonaromatic cycloalkyl groups containing from three to eightcarbon atoms, and other examples include cycloalkyl groups having threeto six carbon atoms. Each cycloalkyl described herein shall beunderstood to be optionally partially or fully halogenated.

The term “aryl” refers to phenyl and naphthyl.

The term “halo” refers to a halogen radical selected from fluoro,chloro, bromo or iodo. Representative halo groups of the invention arefluoro, chloro and bromo.

The term “heteroaryl” refers to a stable 5-8 membered (but preferably, 5or 6 membered) monocyclic or 7-12 membered polycyclic, preferablybicyclic aromatic heterocycle radical. Each heterocycle consists ofcarbon atoms and from 1 to 4 heteroatoms chosen from nitrogen, oxygenand sulfur. The heterocycle may be attached by any atom of the cyclewhich results in the creation of a stable structure. Examples of“heteroaryl” include radicals such as furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl,benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl andphenoxazinyl,

The term “heterocycle” refers to a stable 4-8 membered (but preferably,5 or 6 membered) monocyclic or 7-12 membered polycyclic, preferablybicyclic heterocycle radical which may be either saturated orunsaturated, and is non-aromatic. Each heterocycle consists of carbonatoms and from 1 to 4 heteroatoms chosen from nitrogen, oxygen andsulfur. The heterocycle may be attached by any atom of the cycle, whichresults in the creation of a stable structure. Examples of “heterocycle”include radicals such as pyrrolinyl, pyrrolidinyl, pyrazolinyl,pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl,thiopyranyl, piperazinyl, indolinyl, azetidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrofliranyl, hexahydropyrimidinyl,hexahydropyridazinyl, 1,4,5,6-tetrahydropyrimidin-2-ylamine,dihydro-oxazolyl, 1,2-thiazinanyl-1,1-dioxide,1,2,6-thiadiazinanyl-1,1-dioxide, isothiazolidinyl-1,1-dioxide andimidazolidinyl-2,4-dione.

The terms “heterocycle”, “heteroaryl” or “aryl”, when associated withanother moiety, unless otherwise specified shall have the same meaningas given above. For example, “aroyl” refers to phenyl or naphthyl linkedto a carbonyl group (C═O).

Each aryl or heteroaryl unless otherwise specified includes it'spartially or fully hydrogenated derivative. For example, quinolinyl mayinclude decahydroquinolinyl and tetrahydroquinolinyl, naphthyl mayinclude it's hydrogenated derivatives such as tetrahydranaphthyl. Otherpartially or fully hydrogenated derivatives of the aryl and heteroarylcompounds described herein will be apparent to one of ordinary skill inthe art.

The term heterocycle as it pertains to “Het” shall to be understood tomean a stable nonaromatic spiroheterocycle, 4-8 membered (butpreferably, 5 or 6 membered) monocyclic, 7-12 membered polycyclic,preferably bicyclic heterocycle radical which may be either saturated orunsaturated or a C6-C10O bridged bicyclo wherein one or more carbonatoms are optionally replaced by a heteroatom. Each heterocycle consistsof carbon atoms and from 1 to 4 heteroatoms chosen from nitrogen, oxygenand sulfur. The heterocycle may be attached by any atom of the cycle,which results in the creation of a stable structure. Examples of “Het”include the following heterocycles: azepanyl, piperidinyl, pyrrolidinyl,azetidinyl, oxepanyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrofuranyl, oxetanyl, azocanyl, oxocanyl, 1,3-diazocanyl,1,4-diazocanyl, 1,5-diazocanyl, 1,3-dioxocanyl, 1,4-dioxocanyl,1,5-dioxocanyl, 1,3-oxazocanyl, 1,4-oxazocanyl, 1,5-oxazocanyl,1,3-diazepanyl, 1,4-diazepanyl, 1,3-dioxepanyl, 1,4-dioxepanyl,1,3-oxazepanyl, 1,4-oxazepanyl, 1,2-thiazocanyl-1,1-dioxide,1,2,8-thiadiazocanyl-1,1-dioxide, 1,2-thiazepanyl-1,1-dioxide,1,2,7-thiadiazepanyl-1,1-dioxide, tetrahydrothiophenyl,hexahydropyrimidinyl, hexahydropyridazinyl, piperazinyl, 1,4,56-tetrahydropyrimidinyl, pyrazolidinyl, dihydro-oxazolyl,dihydrothiazolyl, dihydroimidazolyl, isoxazolinyl, oxazolidinyl,1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide,isothiazolidinyl-1,1-dioxide, imidazolidinyl-2,4-dione, imidazolidinyl,morpholinyl, dioxanyl, tetrahydropyridinyl, thiomorpholinyl,thiazolidinyl, dihydropyranyl, dithianyl, decahydro-quinolinyl,decahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, indolinyl,octahydro-quinolizinyl, dihydro-indolizinyl, octahydro-indolizinyl,octahydro-indolyl, decahydroquinazolinyl, decahydroquinoxalinyl,1,2,3,4-tetrahydroquinazolinyl or 1,2,3,4-tetrahydroquinoxalinyl,aza-bicyclo[3.2.1]octane, aza-bicyclo[2.2.1]heptane,aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.2]nonane,aza-bicyclo[2.1.1]hexane, aza-bicyclo[3.1.1]heptane,aza-bicyclo[3.3.2]decane and 2-oxa or 2-thia-5-aza-bicyclo[2.2.1]heptaneeach heterocyclic ring being substituted with one or more R₅. Thesubstituent R₅ is defined above.

As used herein above and throughout this application, “nitrogen” and“sulfur” include any oxidized form of nitrogen and sulfur and thequaternized form of any basic nitrogen.

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustrating preferred embodiments of this invention, and are not to beconstrued as limiting the scope of the invention in any way.

The examples which follow are illustrative and, as recognized by oneskilled in the art, particular reagents or conditions could be modifiedas needed for individual compounds. Starting materials used in thescheme below are either commercially available or easily prepared fromcommercially available materials by those skilled in the art.

GENERAL SYNTHETIC METHODS

The invention also provides processes of making the present novelcompounds. Compounds of the invention may be prepared by methodsdescribed below. Standard peptide coupling, protection and deprotectionreactions (see for example M. Bodanszky, 1984 The Practice of PeptideSynthesis, Springer-Verlag) are employed in these syntheses and areincorporated herein by reference in their entirety.

COMPOUNDS OF THE FORMULAS (I) AND (II)

Compounds of the invention having formulas (I) and (II) may be preparedby Method A as illustrated in Scheme I.

According to Method A a suitably protected amino acid bearing “Het” isallowed to react with ammonia under standard coupling conditions. Anexample of a suitable protecting group is the t-butoxycarbonyl (BOC)group. An example of standard coupling conditions would be combining thestarting materials in the presence of a coupling reagent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) with1-hydroxybenzotriazole (HOBT), in a suitable solvent such as DMF ormethylene chloride. A base such as N-methyltorpholine may be added. Thisis followed by deprotection to give amino acid amide III. An amino acidester (IV) bearing R₂, R₃ and optionally R₄ other than H is then reactedwith an activated acid [R₁C(O)L] such as acid chloride (L=Cl) in thepresence of a suitable base such as N,N-diisopropylethylamine to provideV. Alternately, one may use the carboxylic acid [R₁C(O)L, L=OH] andactivate using standard peptide coupling conditions, such as EDC andHOBT as described above. If R₄ is H in V, one may optionally react Vwith an alkyl halide in the presence of a suitable base such as sodiumhydride, in a suitable solvent such as DMF or THF to provide V in whichR₄ is alkyl. Conversion to the carboxylic acid provides VI. Standardpeptide coupling of III and VI, followed by dehydration of the amideprovides the desired nitrile I or II. An example of suitable dehydrationconditions is cyanuric chloride in DMF.

In a variation (Method B) illustrated in Scheme II, an amino acid amidebearing “Het” is coupled with an amine-protected amino acid bearing R₂and R₃. A suitable protecting group and coupling conditions would be asdescribed above. Deprotection is then followed by reaction with R₁C(O)L(as described in Method A). Conversion of the amide to the nitrile asabove provides I or II.

Compounds of the invention having formula (I) and (II) may also beprepared by Method C as illustrated in Scheme III.

In this variation (Method C) an amino nitrile bearing “Het” is coupledwith an amine protected amino acid bearing R₂ and R₃. A suitableprotecting group and coupling conditions are described above.Deprotection is then followed by reaction with R₁C(O)L as describedabove to furnish the nitrile (I/II).

Compounds of the invention having formulas (I) and (II) may also beprepared by as outlined below in Scheme IV (Method D).

In a further variation (Method D) illustrated in Scheme IV, an aminoacid ester (IV) bearing R₂, R₃ and optionally R₄ other than H is reactedwith R₁C(O)L as described in Method A. Conversion to the carboxylic acidprovides VI. Standard peptide coupling of an amino nitrile bearing “Het”with VI yields the desired nitrile (I/II).

The intermediate aminonitrile used in Methods C, and D above may beprepared as outlined in Scheme V.

In this method, a ketone bearing “Het” is reacted with an a primaryamine or an ammonium salt, such as ammonium chloride, and a cyanidesalt, such as potassium cyanide or sodium cyanide, in a suitablesolvent, such as water or a solution of ammonia in methanol, at aboutroom temperature to reflux temperature.

In each of the methods described above, required starting materials areeither commercially available or easily prepared by those skilled in theart, for example see:

Leung, M.-k.; Lai, J.-L.; Lau, K.-H.-; Yu, H.-h.; Hsiao, J.-J. J. Org.Chem. 1996, 61, 4175-4179.

Mee, J. D. J. Org. Chem. 1975, 40, 2135-2136.

Micovic, I. V.; Roglic, G. M.; Ivanovic, M. D.; Dosen-Micovic, L.;Kiricojevic, V. D.; Popovic, J. B. J. Chem. Soc, Perkin Trans. 1, 1996,2041-2050.

Tornus, I.; Schaumann, E. Tetrahedron 1996, 52, 725-732.

Jadhav, P. K.; Woemer, F. J. Tetrahedron Letters 1995, 36, 6383-6386.

Kochhar, K. S.; et al. Tetrahedron Letters 1984, 25, 1871-1874.

Fordon, K. J.; Crane, C. G.; Burrows, C. J. Tetrahedron Letters 1994,35, 6215-6216. These references are incorporated herein by reference intheir entirety.

COMPOUNDS OF THE FORMULAS (Ia) AND (Ib)

The invention also provides processes of making the present novelcompounds of formula (Ia) and (Ib). Compounds of the invention may beprepared by methods described below.

A key intermediate in the preparation of compounds of formula (Ia) and(Ib) is the dipeptide nitrile intermediate (VII).

The synthesis of intermediates of formula (VII) is described in U.S.provisional patent application Ser. No. 60/153,738 and outlined below inSchemes VI and VII.

As illustrated in Scheme VI, an amino acid bearing a suitable protectinggroup R′ (VIII), is reacted with an amino nitrile (IX) under suitablecoupling conditions. An example of a suitable protecting group is thet-butoxycarbonyl (BOC) group. An example of standard coupling conditionswould be combining the starting materials in the presence of a couplingreagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) with1-hydroxybenzotriazole (HOBT), in a suitable solvent such as DMF ormethylene chloride. A base such as N-methylmorpholine may be added. Thisis followed by deprotection to give amino acid nitrile VII.

The intermediate aminonitrile (IX) used in Scheme VI above may beprepared as outlined in Scheme VII.

In this method, a ketone bearing “Het” (XI) is reacted with an a primaryamine or an ammonium salt, such as ammonium chloride, and a cyanidesalt, such as potassium cyanide or sodium cyanide, in a suitablesolvent, such as water or a solution of ammonia in methanol, at aboutroom temperature to reflux temperature.

Compounds having formula (Ia/Ib) may be prepared by Methods E-H, asillustrated in Schemes VIII-IX.

According to Method E, a dipeptide nitrile intermediate (VII), or abasic salt thereof, is allowed to react with (XII) in the presence of asuitable coupling agent to provide the desired product (Ia/Ib). Suitablereaction conditions are known to those skilled in the art and someexamples of suitable coupling agents include 2-chloro-1-methylpyridiniumiodide (Yong, Y. F. et al., J. Org. Chem. 1997, 62, 1540), phosgene ortriphosgene (Barton, D. H. et al., J. Chem. Soc. Perkin Trans. I, 1982,2085), alkyl halides (Brand, E. and Brand, F. C. , Org. Synth., 1955, 3,440) carbodiimides (Poss, M. A. et al., Tetrathedron Lett., 1992, 40,5933) and mercury salts (Su, W., Synthetic Comm., 1996, 26, 407 andWiggall, K. J. and Richardson, S. K. J., Heterocyclic Chem., 1995, 32,867).

Compounds having formulas (Ia) and (Ib) may also be prepared by Method Bas illustrated in Scheme IV, where R is an alkyl or aryl group.

According to Method F a dipeptide nitrile intermediate (VII), or a basicsalt thereof, is allowed to react with XII, with or without an addedbase such as triethylamine, to provide the desired product (Ia/Ib).Suitable reaction conditions are known to those skilled in the art andexamples of such amine additions may be found in the chemicalliterature, for example Haake, M. and Schummelfeder, B., Synthesis,1991, 9, 753; Dauwe, C. and Buddrus, J., Synthesis 1995, 2, 171; Ried,W. and Piechaczek, D., Justus Liebigs Ann. Chem. 1966, 97, 696 and Dean,W. D. and Papadopoulos, E. P., J. Heterocyclic Chem., 1982, 19, 1117.

The intermediate XII is either commercially available or can besynthesized by methods known to those skilled in the art and describedin the literature, for example Francesconi, I. et. al., J. Med. Chem.1999, 42, 2260; Kurzer, F., Lawson, A., Org. Synth. 1963, 645, andGutman, A. D. U.S. Pat. No. 3,984,410, 1976.

In a similar reaction, intermediate XIV having a halogen or othersuitable leaving group (X) may be used in place of intermediate XIII, asillustrated in Method G, Scheme IX.:

According to Method G, a dipeptide nitrile intermediate, or a basic saltthereof, is allowed to react with intermediate XIV, with or without anadded base such as triethylamine, to provide the desired product(Ia/Ib). Procedures for accomplishing this reaction are knovn to thoseskilled in the art and described in the chemical literature (forexample, Dunn, A. D. , Org. Prep. Proceed. Int., 1998, 30, 709;Lindstroem, S. et al., Heterocycles, 1994 38, 529; Katritzky, A. R. andSaczewski, F., Synthesis, 1990, 561; Hontz, A. C. and Wagner, E. C., OrgSynth., 1963, IV, 383; Stephen, E. and Stephen, H., J. Chem. Soc., 1957,490).

Compounds having formula (Ia/Ib) in which R₁ is an amine may also beprepared by Method H as illustrated in Scheme X.

According to Method H, a carbodiimide (XV) derivative of (VII) isallowed to react with an amine (R₁) to provide the desired guanidine(Ia/Ib) product. The conversion of amines to carbodiimides is known tothose in the art and described in the literature (for example, Pri-Bar,I. and Schwartz, J., J. Chem. Soc. Chem. Commun., 1997, 347; Hirao, T.and Saegusa, T., J. Org. Chem., 1975, 40, 298). The reaction ofcarbodiimides with amine nucleophiles is also described in theliterature (for example, Yoshiizumi, K. et al., Chem. Pharm. Bull.,1997, 45, 2005; Thomas, E. W. et al., J. Med. Chem., 1989, 32, 228;Lawson, A. and Tinkler, R. B., J. Chem. Soc. C, 1971, 1429.

In a modification of Method H, one may start with the thiourea XVI(formed by reaction of the corresponding amine with an isothiocyanateR₆N═C═S) and then form the corresponding carbodiimide (XV) in situ byreaction with a suitable desulfurizing agent, such as HgCl₂, in asuitable solvent such as DMF or acetonitrile.

Compounds of formula (Ib), where R₁ is an amine may be prepared using ageneral procedure described by M. Haake and B. Schummfelder (Synthesis,1991, 753). Acccording to this procedure (Method I, Scheme XI),intermediate XVII bearing two suitable leaving groups Z, such as phenoxygroups, is reacted sequentially with amines R₁ and R₆R₈NH in a suitablesolvent such as methanol or isopropanol to provide the desired product.Reaction of the first amine may be carried out at about room temperatureand reaction of the second amine is preferentially carried out withheating at the reflux temperature of the solvent. If XIII is allowed toreact with a bifunctional nucleophile intermediate XVIII, where Y is anucleophilic heteroatom such as N, O or S, one may obtain the product offormula (Ib) where R₁ and R₆ form a heterocyclic ring. Intermediate XVIImay be prepared by reaction of VII (R₄=H) with dichlorodiphenoxymethane,which in turn, may be prepared by heating diphenyl carbonate with PCl₅(R. L. Webb and C. S. Labow, J. Het. Chem., 1982, 1205).

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustrating embodiments of this invention, and are not to be construedas limiting the scope of the invention in any way.

The examples which follow are illustrative and, as recognized by oneskilled in the art, particular reagents or conditions could be modifiedas needed for individual compounds. Starting materials used in thescheme below are either commercially available or easily prepared fromcommercially available materials by those skilled in the art.

SYNTHETIC EXAMPLES Example 1 Morpholine-4-carboxylic Acid[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) 4-Amino-4-cyano-1-methylpiperidine.

A solution of ammonium chloride (1.89 g, 35.37mmol) and potassiumcyanide (2.30 g, 35.37 mmol) was prepared in 50 mL of water.1-Methyl-4-piperidone (1.0 g, 8.84 mmol) was added to the solution andstirred for 2 days. The solution was brought to pH 11 with solid sodiumcarbonate and the reaction solution was extracted 3×100 mL of EtOAc. Theorganic layer was dried over anhydrous Na₂SO₄, decanted and concentratedto an orange oil (857 mg). ¹H NMR showed that the oil was a 2:1:1mixture of the desired aminonitrile, cyanohydrin and starting ketone.The crude mixture was used in the next step without furtherpurification.

(b) N-(4-Morpholinecarbonyl)-L-cyclohexyl Alanine Methyl Ester.

Methyl L-β-cyclohexylalanine hydrochloride (1.45 g, 6.54 mmol) wasdissolved in 20 mL of DMF and 10 mL of Hunig's base was added to give aclear colorless solution. 4-Morpholinecarbonyl chloride (1.17 g, 7.85mmol) was added and the resulting reaction was stirred at ambienttemperature for 6 h. The reaction mix was concentrated in vacuo and theresidue was taken up in 200 mL of CH₂Cl₂ and washed with 1×100 mL ofEtOAc and 2×100 mL of brine. The organic layer was dried over Na₂SO₄,decanted, and concentrated to a semi-solid (1.86 g) which was used inthe next step without further purification.

(c) N-(4-Morpholinecarbonyl)-L-cyclohexyl Alanine

N-(4-Morpholinecarbonyl)-L-cyclohexyl alanine methyl ester (1.86 g, 6.23mmol) was dissolved in 50 mL of MeOH to which was added 50 mL THF and 50mL of water. LiOH monohydrate (2.61 g, 62.3 mmol) was added to thereaction solution and the reaction was monitored at 5 min and every 20min thereafter using 5% MeOH in CH₂Cl₂. The starting material wasconsumed at 2 h and the reaction was washed with 150 mL of diethyl etherwith the organic layer being discarded. The aqueous layer was brought topH 1 with concentrated HCl and the product was extracted with 2×100 mLof EtOAc. The combined organic layers were dried over Na₂SO₄, decantedand concentrated to white solid foam (1.63 g): ¹H NMR (CDCl₃) δ8.90-7.90 (br, 1H), 5.05-4.99 (m, 1H), 4.55-4.39 (m, 1H), 3.71-3.62 (m,4H), 3.50-3.36 (m, 4H), 1.90-0.83 (m, 13H).

(d) Morpholine-4-carboxylic Acid[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

N-(4-Morpholinecarbonyl)-L-cyclohexyl alanine (350 mg, 1.23 mmol) wasdissolved in 15 mL of DMF. EDC (235 mg, 1.23 mmol) and HOBT (166 mg,1.23 mmol) were added and the resulting mixture was stirred at ambienttemperature for 20 min during which time the solids went into solution.4-Amino-4-cyano-1-methylpiperidine (310 mg of the 2:1:1 mixture ofaminonitrile:cyanohydrin:ketone, ≅1.1 mmol aminonitrile) was dissolvedin 5 mL of DMF, N-methylmorpholine was added to this solution (497 mgs,4.92 mmol), and the resultant solution added to the solution of theactivated ester. The resulting mixture was stirred at ambienttemperature for 16 h. The volatiles were removed in vacuo and theresulting residue was dissolved in 200 mL of EtOAc and washedsequentially with 2×200 mL saturated sodium bicarbonate and 1×100 mLbrine. The organic layer was dried over anhydrous Na₂SO₄, decanted, andconcentrated to a thick oil. The oil was purified by columnchromatagraphy on SiO₂ using as eluent 100% CH₂Cl₂ to 12% MeOH in CH₂Cl₂to give the desired product as a white powder (225 mg): ¹H NMR (CDCl₃) δ7.55 (s, 1H), 5.13-5.08 (m, 1H), 4.40-4.20 (m, 1H), 3.77-3.62 (m, 4H),3.51-3.33 (m, 4H), 2.88-2.55 (m, 2H), 2.53-2.39 (m, 2H), 2.30(s, 3H),2.10-0.83 (m, 17H).

Following the above procedures the following compounds can besynthesised;

Morpholine-4-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-naphtalen-2-yl-ethyl]-amide

Morpholine-4-carboxylic acid[2-(3-chloro-phenyl)-1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethyl]-amide

Morpholine-4-carboxylic acid[2-(4-chloro-phenyl)-1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl) -pentyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3-methyl-1-butyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1-phenyl-2,6-dioxo-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1-phenyl-2,6-dioxo-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-2-oxo-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-2-oxo-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1-methyl-2-oxo-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1-methyl-2-oxo-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(5-cyano-1,1-dioxo-1λ⁶-[1,2]thiazinan-5ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(5-cyano-1,1-dioxo-1λ⁶-[1,2]thiazinan-5-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(5-cyano-2-methyl-1,1-dioxo-1λ⁶-[1,2]thiazinan-5-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(5-cyano-2-methyl-1,1-dioxo-1λ⁶-[1,2]thiazinan-5-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(5-cyano-2-oxo-hexahydro-pyrimidin-5-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(5-cyano-1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-2,6-dimethyl-1,1-dioxo-1λ⁶-[1,2,6]thiadiazinan-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(3-cyano-5-oxo-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(3-cyano-1-methyl-5-oxo-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(3-cyano-5-oxo-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(3-cyano-1-methyl-5-oxo-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Example 2 Morpholine-4-carboxylic Acid[1-(4-Cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) 4-Amino-4-cyano-tetrahydropyran.

A solution of ammonium chloride (2.12 g, 39.57 mmol) and potassiumcyanide (2.58 g, 39.57 mmol) was prepared in 50 mL of water.Tetrahydropyran-4-one (1.0 g, 9.89 mmol) was added to the solution andstirring was continued for 2 days. The solution was brought to pH 11with solid sodium carbonate and the reaction solution was extracted3×100 mL of EtOAc. The organic layer was dried over anhydrous Na₂SO₄,decanted, and concentrated to an clear oil (1.02 g). ¹H NMR showed thatthe oil was a 7 to 1 mixture of the desired aminonitrile andcyanohydrin. The crude mixture was used in the next step without furtherpurification.

(b) Morpholine-4-carboxylic Acid[1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide.

N-(4-morpholinecarbonyl)-L-cyclohexyl alanine (350 mg, 1.23 mmol) wasdissolved in 15 ml of DMF. EDC (235 mg, 1.23 mmol) and HOBT (166 mg,1.23 mmol) were added and the resulting mixture was stirred at ambienttemperature for 20 min during which time the solids went into solution.4-Amino-4-cyano-tetrahydropyran (161 mg of the 7:1 mixture ofaminonitrile, ≅1.1 mmol aminonitrile) was dissolved in 5 mL of DMF,N-methylmorpholine was added to this solution (497 mgs, 4.92 mmol), andthe resultatnt solution added to the solution of the active ester. Theresulting mixture was stirred at ambient temperature for 16 h. Thevolatiles were removed in vacuo and the resulting residue was vigorouslystirred for 30 min with 100 mL of a 1 to 1 mixture of water andsaturated sodium bicarbonate to give a fluffy white solid that wascollected by filtration. The solid was washed with 3×50 mL of water anddried to give the desired product (210 mg): ¹H NMR (CDCl₃) δ 7.80 (s,1H), 5.25-5.15 (m, 1H), 4.41-20 (m, 1H), 3.97-3.62 (m, 8H), 3.50-3.41(m, 4H), 2.50-2.37 (m 1H), 2.35-2.20 (m, 1H), 2.05-1.88 (m, 2H),1.79-0.75 m, 13H).

Example 34-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicAcid Ethyl Ester

(a) 4 Amino-4-cyano-piperidine-1-carboxylic Acid Ethyl Ester.

A solution of ammonium chloride (31 g, 584 mmol) and potassium cyanide(7.61 g, 116 mmol) was prepared in 250 mL of water.1-(Ethoxycarbonyl)-4-piperidone (10 g, 58.4 mmol) was added to thesolution followed by 50 mL of MeOH and stirring was continued for 3days. The solution was brought to pH 11 with solid sodium carbonate (20g and the reaction solution was extracted with 3×250 mL of EtOAc. Theorganic layers were combined, dried over Na₂SO₄, decanted andconcentrated to an thick oil. The oil was triturated with 500 mL ofhexane and the resulting solid was collected by filtration (8.3 g). ¹HNMR showed that the product was better than 95% pure.

(b)4-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicAcid Ethyl Ester

N-(4-morpholinecarbonyl)-L-cyclohexyl alanine (555 mg, 1.95 mmol) wasdissolved in 15 ml of DMF. EDC (373 mg, 1.95 mmol) and HOBt (264 mg,1.95 mmol) were added and the resulting mixture was stirred at ambienttemperature for 20 min during which time the solids went into solution.4-Amino-4-cyano-piperidine-1-carboxylic acid ethyl ester (350 mg, 1.77mmol) was dissolved in 5 mL of DMF and added to the solution of theactive ester followed by addition of 2 mL of N-methylmorpholine. Theresulting mixture was stirred at ambient temperature for 16 h. Thevolatiles were removed in vacuo and the resulting residue was dissolvedin 200 mL of EtOAc and washed sequentially with 2×200 mL saturatedsodium bicarbonate, 1×100 mL brine. The organic layer was dried overNa₂SO₄, decanted, and concentrated to a white solid. The solid waspurified by column chromatagraphy on SiO₂ using as eluent 100% CH₂Cl₂ to5% MeOH in CH₂Cl₂ to give the title compound as a white powder (511 mg):m.p. 140-143° C.

Example 4 Morpholine-4-carboxylic Acid[1-(4-Cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) 4-Amino-4-cyano-1-phenethylpiperidine was prepared according to theprocedure from Example 1, step a, starting with1-phenylethyl-4-piperidone.

(b) The title compound was prepared starting fromN-(4-Morpholinecarbonyl)-L-cyclohexyl alanine and4-amino-4-cyano-1-phenethylpiperidine according to the procedure fromExample 2, step b, except that the compound was purified by HPLC using a20×250 mm C₁₈ reverse phase column with the method being 30%acetonitrile in water to 100% acetonitrile. MS, m/z 496=M+1.

Example 5 Morpholine-4-carboxylic Acid[1-(1-Benzyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) 4-Amino-4-cyano-1-benzylpiperidine was prepared according to theprocedure from example 1, step a, starting with 1-benzyl-4-piperidone

(b) The title compound was prepared starting fromN-(4-Morpholinecarbonyl)-L-cyclohexyl alanine and4-amino-4-cyano-1-benzylpiperidine according to the procedure fromExample 2, step b, except that the compound was purified by HPLC using a20×250 n an C₁₈ reverse phase column with the method being 30%acetonitrile in water to 100% acetonitrile. MS, m/z 482=M+1.

Example 6 Morpholine-4-carboxylic Acid[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) 4-Amino-4-cyano-1-propylpiperidine was prepared according to theprocedure from Example 1, step a, starting with 1-propyl-4-piperidone.

(b) The title compound was prepared starting fromN-(4-Morpholinecarbonyl)-L-cyclohexyl alanine and4-amino-4-cyano-1-propylpiperidine according to the procedure fromExample 2, step b, except that the compound was purified by HPLC using a20×250 mm C₁₈ reverse phase column with the method being 30%acetonitrile in water to 100% acetonitrile. MS, m/z 434=M+1.

Example 74-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicAcid Benzyl Ester

(a) A solution of sodium cyanide (1052 mg, 21.5 mmol), ammonium chloride(1265 mg, 3.65 mmol), and benzyl 4-oxo-1-piperidine-carboxylate (5.0 gm,21.5 mmol), was prepared in 5 M ammonia in methanol (8.6 mL, 43 mmol).The solution was brought to reflux for 4 h and then allowed to cool toroom temperature, The solution was then filtered and washed withmethanol (100 mL) and the filtrate was concentrated in vacuo. Theresulting oil was taken up in MTBE (250 mL) and filtered again. Thefilter cake was washed with MTBE (100 mL) and the filtrate wasconcentrated in vacuo to yield 4-amino-4-cyano-piperidine-1-carboxylicacid benzyl ester as a clear oil (3.5 g) which was used without furtherpurification.

(b) The title compound was prepared starting fromN-(4-Morpholinecarbonyl)-L-cyclohexyl alanine and4-amino-4-cyano-piperidine-1-carboxylic acid benzyl ester according tothe procedure from Example 2, step b, except that the compound waspurified by HPLC using a 20×250 mm C₁₈ reverse phase column with themethod being 30% acetonitrile in water to 100% acetonitrile. MS, m/z526=M+1.

Example 8 Morpholine-4-carboxylic Acid[1-(4-Cyano-tetrahydro-thiopyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) 4-Amino-tetrahydro-thiopyran-4-carbonitrile was prepared accordingto the procedure from Example 7, step a, starting fromtetrahydrothiopyran-4-one.

(b) The title compound was prepared starting fromN-(4-Morpholinecarbonyl)-L-cyclohexyl alanine and4-amino-4-cyano-tetrahydrothiopyrane according to the procedure fromExample 2, step b, except that the compound was purified by reversephase HPLC using a 20×250 mm C₁₈ reverse phase column with the methodbeing 30% acetonitrile in water to 100% acetonitrile. MS, m/z 409=M+1.

Example 9 Morpholine-4-carboxylic Acid[1-(4-Cyano-1-pyrimidin-2-yl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) 4-Amino-4-cyano-1-pyrimidin-2-yl-piperidine was prepared accordingto the procedure from Example 7, step a, starting with1-(pyrimidin-2-yl)-4-piperidone with the exception that a 2 M ammonia inmethanol solution replaced the 5 M ammonia in methanol solution.

(b) The title compound was prepared starting fromN-(4-Morpholinecarbonyl)-L-cyclohexyl alanine and4-amino-4-cyano-1-pyrimidin-2-yl-piperidine according to the procedurefrom Example 2, step b, except that the compound was purified by HPLCusing a 20×250 mm C₁₈ reverse phase column with the method being 30%acetonitrile in water to 100% acetonitrile. MS, m/z 469=M+1.

Example 10 Morpholine-4-carboxylic Acid[1-(4-Cyano-2,6-diphenyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) 4-Amino-4-cyano-2,6-diphenyl-piperidine was prepared according tothe procedure from Example 9, step a, starting from2,6-diphenyl-4-piperidone.

(b) The title compound was prepared starting fromN-(4-Morpholinecarbonyl)-L-cyclohexyl alanine and4-amino-4-cyano-2,6-diphenyl-piperidine according to the procedure fromExample 2, step b, except that the compound was purified by HPLC using a20×250 mm C₁₈ reverse phase column with the method being 30%acetonitrile in water to 100% acetonitrile. MS, m/z 544=M+1.

Example 11 Morpholine-4-carboxylic Acid[1-(4-Cyano-2,6-diphenyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

(a) -Amino-4,4-dimethyl-pentanoic Acid Methyl Ester

2-Amino-4,4-dimethyl-pentanoic acid (1.00 g, 6.84 mmol) was suspended in50 mL of methanol and cooled in an ice bath. Thionyl chloride (1.82 g,15.0 mmol) was added dropwise, at which time all the acid went intosolution. The reaction was then removed from the ice bath and heated toreflux for 3.5 h. The reaction mixture was concentrated in vacuo and theresulting solid (1.10 g) was used in the next step without furtherpurification. MS, m/z 159.9=M+1.

(b) 4,4-Dimethyl-2-[(morpholine-4-carbonyl)-amino]-pentanoic Acid MethylEster

2-Amino-4,4-dimethyl-pentanoic acid methyl ester (5.35 g, 27.4 mmol) wasdissolved in 100 mL of dichloromethane. Hunig's base (7.07 g, 54.7 mmol)and 4-morpholinecarbonyl chloride (4.08 g, 27.4 mmol) were added and thereaction was stirred at ambient temperature 16 h. The reaction mixturewas concentrated in vacuo and taken up in 150 mL EtOAc. A whiteprecipitate formed and was filtered and washed with EtOAc. EtOAcsolutions were combined and washed with 3×50 mL 1 N HCl (aq), 3×50saturated NaHCO₃ (aq), and 1×50 mL brine. The organic layer was driedover Na₂SO₄, decanted, and concentrated to a white solid (6.33 g). MS,m/z 273=M+1.

(c) N-(4-Morpholinecarbonyl)-L-neopentyl Glycine

4,4-Dimethyl-2-[(morpholine-4-carbonyl)-amino]-pentanoic acid methylester (6.33 g, 23.2 mmol) was dissolved in 100 mL of THF and 50 mL ofmethanol. The solution was cooled on an ice bath and lithium hydroxidemonohydrate (5.80 g, 116 mmol) was added as a suspension in 50 mL ofwater. The reaction was stirred at ambient temperature for 1 h.Additional water was added to the reaction (25 mL) and the mixture wasextracted with diethyl ether 2×75 mL. The organic layer was discarded.The aqueous layer was acidified to pH 2 with 20% HCl (aq) and theproduct was extracted with 3×75 mL EtOAc. The EtOAc layer was washedwith 1×50 mL brine and dried over Na₂SO₄, decanted, and concentrated invacuo to a white solid (5.85 g). MS, m/z 259=M+1.

(d) Morpholine-4-carboxylic Acid[1-(4-Cyano-2,6-diphenyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

N-(4-morpholinecarbonyl)-L-neopentyl glycine (214 mg, 0.83 mmol) wasdissolved in 25 mL of dichloromethane. EDC (175 mg, 0.91 mmol), HOBT(123 mg, 0.91 mmol), 4-amino-4-cyano-2,6-diphenylpiperidine (Example 10)(278 mg, 0.91 mmol), and N-methylmorpholine (420 mg, 4.2 mmol) wereadded to the solution. The reaction was stirred at ambient temperaturefor 16 h. The reaction was concentrated in vacuo and the resultingresidue was dissolved in 150 mL of EtOAc. The EtOAc layer was washedwith 2×50 mL saturated NaHCO₃, 1×50 mL brine, then dried over Na₂SO₄,decanted, and concentrated to an oil. Product was recrystallized fromEtOAc/hexanes to yield a white solid (42 mg). MS, m/z 518=M+1.

Example 12 Morpholine-4-carboxylic Acid[(1-Acetyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) 4-Amino-4-cyano-1-acetylpiperidine was prepared according to theprocedure from example 9, step a, starting with 1-acetyl-4-piperidone.

(b) The title compound was prepared starting fromN-(4-morpholinecarbonyl)-L-cyclohexyl alanine and4-amino-4-cyano-1-acetylpiperidine according to the procedure fromExample 2, step b, except that the compound was purified by HPLC using a20×250 1 C₁₈ reverse phase column with the method being 30% acetonitrilein water to 100%, acetonitrile. MS, m/z 433=M+1.

Example 13 Morpholine-4-carboxylic Acid[1-(4-Cyano-tetrahydro-pyran-4-ylcarbamoyl -3,3-dimethyl-butyl]-amide

(a) 4-Amino-4-cyano-tetrahydropyran was prepared according to theprocedure from Example 1, step a, starting from tetrahydropyran-4-one.

(b) The title compound was prepared starting fromN-(4-morpholinecarbonyl)-L-neopentyl glycine (Example 1 1, step c) and4-amino-4-cyano-tetrahydropyrane according to the procedure from Example2, step b, except that the compound was purified by HPLC using a 20×250mm C₁₈ reverse phase column with the method being 30% acetonitrile inwater to 100% acetonitrile. MS, m/z 367=M+1.

Example 14 Morpholine-4-carboxylic Acid[1-(4-Cyano-tetrahydro-thiopyran-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

The title compound was prepared starting fromN-(4-Morpholinecarbonyl)-L-neopentyl glycine (Example 11, step c) and4-amino-4-cyano-tetrahydrothiopyran (Example 8) according to theprocedure from Example 1, step d, except that the compound was purifiedby HPLC using a 20×250 mm C₁₈ reverse phase column with the method being30% acetonitrile in water to 100% acetonitrile. MS, m/z 383=M+1.

Example 15 Morpholine-4-carboxylic Acid[1-(1-Benzyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

The title compound was prepared starting fromN-(4-Morpholinecarbonyl)-L-neopentyl glycine (Example 11, step c) and4-amino-4-cyano-1-benzylpiperidine (Example 5, step a) according to theprocedure from Example 1, step d, except that the compound was purifiedby HPLC using a 20×250 mm C₁₈ reverse phase column with the method being30% acetonitrile in water to 100% acetonitrile. MS, m/z 456=M+1.

Example 16 Morpholine-4-carboxylic Acid[1-(1-Isopropyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

(a) 4-Amino-4-cyano-1-isopropylpiperidine was prepared according to theprocedure from example 1, step a, starting from 1-i-propyl-4-piperidone.

(b) The title compound was prepared starting fromN-(4-morpholinecarbonyl )-L-neopentyl glycine (Example 11, step c) and4-amino -4-cyano -1-isopropylpiperidine according to the procedure fromExample 1, step d, except that the compound was purified by HPLC using a20×250 mm C₁₈ reverse phase column with the method being 30%acetonitrile in water to 100% acetonitrile. MS, m/z 456=M+1.

Example 17 Morpholine-4-carboxylic Acid[1-(1-Phenethyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

The title compound was prepared starting fromN-(4-morpholinecarbonyl)-L-neopentyl glycine (Example 11, step c) and4-amino-4-cyano-1-phenethylpiperidine (Example 4) according to theprocedure from Example 1, step d, except that the compound was purifiedby HPLC using a 20×250 mm C₁₈ reverse phase column with the method being30% acetonitrile in water to 100% acetonitrile. MS, m/z 470=M+1.

Example 18 Morpholine-4-carboxylic Acid[1-(1-n-Propyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

The title compound was prepared starting fromN-(4-morpholinecarbonyl)-L-neopentyl glycine (Example 11, step c) and4-amino-4-cyano-1-n-propylpiperidine (Example 6) according to theprocedure from Example 1, step d, except that the compound was purifiedby HPLC using a 20×250 mm C₁₈ reverse phase column with the method being30% acetonitrile in water to 100% acetonitrile. MS, m/z 408=M+1.

Example 194-Cyano-4-{3,3-dimethyl-2-[(morpholine-4-carbonyl)-amino]-pentanoylamino}-piperdine-1-carboxylicAcid Benzyl Ester

The title compound was prepared starting fromN-(4-morpholinecarbonyl)-L-neopentyl glycine (Example 11, step c) and4-amino-4-cyano-piperidine-1-carboxylic acid benzyl ester Example 7,step a) according to the procedure from Example 1, step d, except thatthe compound was purified by HPLC using a 20×250 mm C₁₈ reverse phasecolumn with the method being 30% acetonitrile in water to 100%acetonitrile. MS, m/z 500=M+1.

Example 20 Morpholine-4-carboxylic Acid[1-(1-Acetyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

(a) 1-Acetyl-4-amino-piperidin-4-carbonitrile

1-Acetyl-4-amino-piperidin-4-carbonitrile was prepared fromN-acetyl-4-piperidone according to the procedure from Example 9, step a.

(b) The title compound was prepared starting from1-Acetyl-4-amino-piperidine-4-carbonitrile andN-(4-morpholinecarbonyl)-L-neopentyl glycine (Example 11, step c)according to the procedure from Example 11, step d and purified byreverse phase HPLC (43 mg). MS, m/z 408=M+1.

Example 21 Morpholine-4-carboxylic Acid[1-(1-Benzoyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

(a) 4-Amino-1-benzoyl-piperidine-4-carbonitrile was prepared fromN-benzoyl-4-piperidone according to the procedure from Example 9, stepa. MS, m/z 168=M+1

(b) The title compound was prepared starting from4-amino-1-benzoyl-piperidine-4-carbonitrile andN-(4-morpholinecarbonyl)-L-neopentyl glycine (Example 11, step c)according to the procedure from Example 11, step d and purified byreverse phase HPLC (66 mg). MS, m/z 470=M+1

Example 224-Cyano-4-{4,4-dimethyl-2-[(morpholine-4-carbonyl)-amino]-pentanoylamino}-piperidine-1-carboxylicAcid Ethyl Ester

(a) 4-Amino-4-cyano-piperidine-1-carboxylic acid ethyl ester wasprepared according to the procedure from Example 1, step a, from4-oxopiperidine-1-carboxylic acid ethyl ester.

(b) The title compound was prepared starting from4-Amino-4-cyano-piperidine-1-carboxylic acid ethyl ester andN-(4-morpholinecarbonyl)-L-neopentyl glycine (Example 11, step c)according to the procedure from Example 11, step d and purified byreverse phase HPLC (67 mg). MS, m/z 438=M+1

Example 23 Morpholine-4-carboxylic Acid{1-[4-Cyano-1-(2-dimethylamino-acetyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

The title compound was prepared from N,N-dimethylaminoglycine andmorpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidehydrochloride using the coupling method described in Example 1-part (d).The product was purified by reverse phase preparative HPLC to give thetitle compound as an off-white solid; MS, m/z 477=M+1.

Example 24

4-Acetylamino-N-[1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide

(a) t-Butoxycarboxylic Acid[1-(4-Cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide.

t-Butoxycarboxylic acid[1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amid wasprepared from N-Boc-L-cyclohexylalanine and4-amino-4-cyano-tetrahydropyran by the method of Example 2-part (b). Theproduct was used in the next step without further purification.

(b)[1-(4-Cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amineHydrochloride.

t-Butoxycarboxylic acid[1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide(1000 mg, 2.62 mmol) was dissolved in 15 mL of 4 M HCl in dioxane. Thesolution was stirred at ambient temperature for 1 hr. The volatiles wereremoved in vacuo and the resulting paste was triturated with 25 mL ofdiethyl ether to give a fine white solid that was collected byfiltration and dried in vacuo. The product was used without furtherpurification.

(c) 4Acetylamino-N-[1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide.

4-Acetamidobenzoic acid (353 mg, 1.98 mmol), EDC (378 mg, 1.98 mmol),and HOBT (268 mg, 1.98 mmol) were combined in 15 mL of DMF and stirredfor 20 min. Solid[1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-aminehydrochloride (625 mg, 1.98 mmol) was added. The reaction was stirredfor 16 hours. The volatiles were removed with a pump and the resultingresidue was triturated, with rapid stirring, with 250 mL of saturatedaqueous sodium bicarbonate. The resulting solid was collected byfiltration and washed with 250 mL of water. The solid was dried in vacuoto give the title compound (250 mg); MS, ml/z 441=M+1.

Following the above procedures the following compounds can besynthesised;

4-Chloro-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide

N-[1-4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-4-methoxy-benzamide

N-[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-isonicotinamide

Pyrazine-2-carboxylic acid[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

N-[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-3-phenoxy-benzamide

Furan-2-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Thiophene-2-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

5-Chloro-thiophene-2-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(2-thiophen-2-yl-acetylamino)-propionamide.

Example 25 Morpholine-4-carboxylic Acid[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

(a) t-Butoxycarboxylic Acid[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide.

t-Butoxycarboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amidewas prepared from N-Boc-L-neopentylglycine and4-amino-4-cyano-1-methyl-piperidine by a method analogous to that ofExample 2-part (b). The product was used without further purification.

(b)[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amineDihydrochloride.

[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-aminedihydrochloride was prepared by a method analogous to that of Example24-part (b). The product was used without further purification.

(c) Morpholine-4-carboxylic Acid[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide.

[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-aminedihydrochloride (350 mg, 1.03 mmol) was mixed in 10 mL of DMF to whichwas added 1 mL of N-methyl morpholine followed by addition of4-morpholine carbonyl chloride (180 mg, 1.20 mmol) as a solution in 5 mLof DMF. The reaction was stirred for 16 hours at which time thevolatiles were removed in vacuo. The residue was redissolved in 150 mLof EtOAc and washed sequentially with 50 mL of saturated aqueousbicarbonate and 50 mL of brine. The organic layer was dried over sodiumsulfate, decanted and concentrated. The product was purified by flashchromatography on silica gel using 100% methylene chloride to 12%methanol in methylene chloride as eluent to give the title compound as athick oil (85 mg); MS, m/z 380=M+1.

Following the above procedures the following compounds can besynthesised;

4-Chloro-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-benzamide

N-[1-4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-4-methoxy-benzamide

N-[1-4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-isonicotinamide

Pyrazine-2-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Furan-2-carboxylic Acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Thiophene-2-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

4,4-Dimethyl-2-(2-thiophen-2-yl-acetylamino)-pentanoic acid(4-cyano-1-methyl-piperidin-4-yl)-amide

N-[1-4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-3-phenoxy-benzamide

5-Chloro-thiophene-2-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide.

Example 264-Acetylamino-N-1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide

The tile compound was prepared by a method analogous to that of Example24; MS, m/z 454=M+1.

Example 274-Acetylamino-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-buty]-bezamide

The title compound was prepared by a method analogous to that of Example24; MS, m/z 428=M+1.

Example 284-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicAcid t-Butyl Ester

(a) 4-Amino-4-cyano-piperidine-1-carboxylic Acid t-Butyl Ester.

4-Amino-4-cyano-piperidine-1-carboxylic acid t-butyl ester was preparedby a method analogous to that of Example 3-part (a). The product wasused without further purification.

(b)4-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicAcid t-Butyl Ester.

4-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicacid t-butyl ester was prepared by a method analogous to that of Example3-part (b); MS, m/z 391, M− t-butoxycarbonyl).

Example 29 Morpholine-4-carboxylic Acid[1-(4-Cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amideHydrochloride

4-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicacid t-butyl ester (1000 mg, 2.03 mmol) was dissolved in 20 mL of 4 MHCl in dioxane and stirred for 1 hour at which time the volatiles wereremove in vacuo. The resulting residue was triturated with 100 mL ofdiethyl ether and the resulting solid was collected by filtration underinert atmosphere (the solid is very hygroscopic) and washed 2×50 mL ofdiethyl ether and dried in vacuo to yield the title compound as a brightwhite powder (802 mg); MS, m/z 392, M−35).

Example 30 Morpholine-4-carboxylic Acid{1-[4-Cyano-1-(1-methyl-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

(a) 4-Amino-4-cyano-1-(1-methyl-ethyl)-piperidine.

4-Amino-4-cyano-1-(1-methyl-ethyl)-piperidine was prepared by a methodanalogous to that of Example 1-part (a). The product was used withoutfurther purification.

(b) Morpholine-4-carboxylic Acid{1-[4-Cyano-1-(1-methyl-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide.

Morpholine-4-carboxylic acid{1-[4-cyano-1-(1-methyl-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amidewas prepared by a method analogous to that of Example 1-part (d); MS,m/z 434=M+1.

Example 31 Morpholine-4-carboxylic Acid{1-[3-Cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

(a) 3-Amino-3-cyano-1-benzylpyrrolidine.

3-Amino-3-cyano-1-benzylpyrrolidine was prepared by a method analogousto that of Example 1-part (a) with the exception that no sodiumcarbonate was added to the reaction mixture. The product was extractedfrom the crude reaction with 3×100 mL of EtOAc and was used withoutpurification.

(b) Morpholine-4-carboxylic Acid{1-[3-Cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide.Separated Diastereomers.

Diastereomeric morpholine-4-carboxylic acid{1-[3-cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amidewas prepared by a method analogous to that of Example 1-part (d). Thepurification was done by reverse phase preparative HPLC (HypersilHyPURITYTM,C18 column, 250×21.25μ) to separate the two diastereomers;MS, m/z 468=M+1.

Example 32 Morpholine-4-carboxylic Acid[1-(4-Cyano-2,6-dimethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) cis-2,6-Dimethyl-4-piperidone.

Into mixture of dimethyl acetonedicarboxylate (10 g, 57.4 mmol) andacetaldehyde (4.4 g, 100 mmol) maintained at −25° C. was bubbled ammoniauntil the solution was saturated (careful bubbling required due toexothermic dissolution of NH₃). The resulting solution was stored at 0°C. for 20 hours, by which time it was a white sludge. To this was added25 mL of 3 N hydrochloric acid and the solution was heated on thesteam-bath. Carbon dioxide began to evolve soon, but after 24 hours wasstill evolving very slowly. The solution was evaporated almost todryness. To the tan heavy precipitate was added 25 mL of water and thesolution was again evaporated. To the residue was added a solution of 10g of sodium carbonate in 45 mL of water and 20 mL of chloroform. Thelayers were shaken and separated. The water layer was extra ted sixtimes with 20 mL protions of methylene chloride. The organic layers weredried over magnesium sulfate and concentrated to give the desired crudeproduct which was used without further purification.

(b) 4-Amino-4-cyano-2,6-dimethyl-piperidine.

To a mixture of ammonium chloride (0.58 g, 9.98 mmol), sodium cyanide(0.50 g, 11.0 mmol), ammonium hydroxide (2 mL) was added a solution ofcis-2,6-dimethylpiperidone (1.27 g, 9.98 mmol) in 5 mL of methanol. Theresulting mixture was refluxed for 4 hours. The reaction mixture wasevaporated to dryness and the residue was taken up in 50 mLEtOAc, washedwith saturated sodium bicarbonate 3×50 mL. The organic layer wasevaporated to dryness and purified by flash chromatography on silica gelusing 90 to 9 methylene chloride and methanol to give the desiredproduct.

(c) Morpholine-4-carboxylic Acid[1-(4-Cyano-2,6-dimethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide.

The title compound was prepared by the standard method of Example 1-part(d); MS, m/z 420=M+1.

Example 33 Morpholine-4-carboxylic Acid[1-(4-Cyano-1,3-dimethyl-piperidin-4-ylcarbamoyl)-2-Cyclohexyl-ethyl]-amide

(a) 1,3-Dimethyl-4-piperidone Hydrochloride.

To a solution of methylamine (100 mL of 2.0 M solution in methanol) wasadded, over the course of 1 hour at 0° C., a solution of methylmethacrylate (30.2 g, 300 mmol) in 20 mL of methanol. The resultingsolution was allowed to stand for three days, at which time thevolatiles were removed on a rotovap and the residue was vacuum distilledto give the desired product as a clear oil, b.p. 48-49 C. at 8.5 mm. Theoil was dissolved in 100 mL of methanol and methyl acrylate (14.8 g, 200mmol) was added and the reaction was allowed to stand for 3 days. Thevolatiles were removed.

30 ml, of Xylene was prepared over sodium (2.42 g) and refluxed for 2hours and cooled to 60° C. To this mixture was added the diester and thereaction was refluxed until the sodium particles had disappeared. Theresulting dark red liquid was cooled and poured into 150 mL of icewater. The phases were separated and the xylene extracted with 50 mL ofconcentrated hydrochloric acid and, after washing with 50 mL ofisopropyl ether, the aqueous layer was cooled, basified with potassiumcarbonate and extracted eight times with 75 mL portions of ethyl ether.The combined ethereal extracts were dried over potassium carbonate andtreated with excess dry ethereal hydrogen chloride; the resulting saltwas filtered and dried.

The salt was taken up in 60 mL of 6 N hydrochloric acid and heated on awater bath for three hours, at the end of which time the initiallyvigorous carbon dioxide evolution had become negligible. The resultingsolution was evaporated to dryness and dried in vacuo, to yield1,3-dimethyl-4-piperidone hydrochloride (5 g) which was used in the nextstep without further purification.

(b) 4-Amino-4-cyano-1,3-dimethylpiperidine.

The title compound was prepared as described in the previous example for4-amino-4-cyano-2,6-dimethylpiperidine. The crude product was used inthe next step without further purification.

(c) Morpholine-4-carboxylic Acid[1-(4-Cyano-1,3-dimethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide.

The title compound was prepared as in Example 1-part (d); MS, m/z420=M+1.

Example 344-Cyano-4-{3-cyclohexyl-2-[({4-acetylamino}-phenyl-1-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicAcid Ethyl Ester

The title compound was prepared by a method analogous to that of Example24; MS, m/z 512=M+1.

Example 354-Acetylamino-N-[1-(4-cyano-1-benzyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide

The title compound was prepared by a method analogous to that of Example24; MS, m/z 530=M+1.

Example 364-Acetylamino-N-{1-[4-cyano-1-(1-methyl-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-benzamide

The title compound was prepared by the method of Example 24; MS, m/z482=M+1.

Example 37 Morpholine-4-carboxylic Acid{1-[3-Cyano-1-benzyl-piperidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

The title compound, separated into two diastereomers, was prepared by amethod analogous to that of Example 31; MS, m/z 482=M+1.

Example 384-Cyano-4-{3-cyclohexyl-2-[({4-acetylamino}-phenyl-1-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicAcid Benzyl Ester

The title compound was prepared by a method analogous to that of Example24; MS, m/z 574=M+1.

Example 39N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide

The title compound was prepared by a method analogous to that of Example24; MS, m/z 397=M+1.

Example 404-Acetylamino-N-{1-[4-cyano-1-(2-phenyl-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-benzamide

The title compound was prepared by a method analogous to that of Example24; MS, m/z 544=M+1.

Example 414-(Acetylamino-methyl)-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide

(a) 4-(Acetylamino-methyl)-benzoic Acid.

Methyl-4-(acetylamino-methyl)-benzoate was prepared from acetic acid andmethyl 4-(aminomethyl)benzoate using a method analogous to that ofExample 1-part (d). The crude N-acyl ester was saponified using a methodanalogous to that of Example 1-part (c). The crude product was usedwithout further purification.

(b)4-(Acetylamino-methyl)-N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-benzamide.

The title compound was prepared by a method analogous to that of Example24-part (c); MS, m/z 468=M+1.

Example 42 Morpholine-4-carboxylic Acid[1-(3-Cyano-8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) 3-Amino-3-cyano-8-methyl-8-aza-bicyclo [3.2.1]octane.

The aminonitrile was prepared from tropinone using a method analogous tothat of Example 1-part a).

(b) Morpholine-4-carboxylic Acid[1-(3-Cyano-8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide.

The title compound was prepared using a method analogous to that ofExample 1-part (d); MS, m/z 432=M+1.

Example 43 Morpholine-4-carboxylic Acid[1-(1-Carbamimidoyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidep-Toluenesulfonate

(a) 1-Carbamimidoyl-1,2,3-benztriazole p-Toluenesulfonate.

A mixture of benztriazole (11.9 g, 100 mmol), cyanamide (4.2 g, 100mmol), and p-toluene sulfonic acid hydrate (19.2 g, 100 mmol) in dioxanewas refluxed for 24 hours. The reaction mixture was allowed to cool toroom temperature and was diluted with ether, stirred vigorously, thenfiltered. The filter cake was washed with ether and recrystallized fromethanol to give the desired product as a white solid.

(b) Morpholine-4-carboxylic Acid[1-(1-Carbamimidoyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidep-Toluenesulfonate.

Morpholine-4-carboxylic Acid[1-(4-Cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidehydrochloride (0.2 g, 0.47 mmol) was dissolved in 3 mL of DMF and 2equiv of Hunig's base was added followed by1-carbamimidoyl-1,2,3-benztriazole p-toluenesulfonate (0.16 g, 0.47mmol). The reaction was stirred 24 hours at which time the solvent wasremoved in vacuo. The resulting paste was purified by preparative HPLCto give the title compound; MS, m/z 434, M+1− p-toluene sulfonate).

Example 444-Acetylamino-N-[1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-3,3-dimethyl-butyl]-benzamide

4-Amino-4-cyano-tetrahydropyran prepared according to the procedure fromExample 1, step, a, starting from tetrahydropyran-4-one.

The title compound was prepared from 4-amino-4-cyano-tetrahydropyran,L-neopenyyl glycine and 4-acetylaminobenzoic acid analogous to theprocedure described in Example 24.

Example 45 Morpholine-4-carboxylic Acid[1-(4-Cyano-1-methanesulfonyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide.

The title compound is prepared by treatment of morpholine-4-carboxylicacid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidehydrochloride with methanesulfonyl chloride and a tertiary amine basesuch as N-methylmorpholine in a solvent such as methylene chloride.

Example 46 4-Acetylamino-piperidine-1-carboxylic Acid[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide.

The title compound is prepared by a method analogous to that of Example24.

Example 47 Morpholine-4-carboxylic Acid{1-[1-(2-Chloro-benzyl)-3-cyano-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide.

The title compound is prepared by a method analogous to that of Example31.

Example 48 Morpholine-4-carboxylic Acid[1-(1-Benzylcarbamoyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide.

The title compound is prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amidehydrochloride and benzyl isocyanate in the presence of a tertiary aminebase such as N-methylmorpholine in a solvent such as methylene chloride.

Example 49 Morpholine-4-carboxylic Acid[1-(1-Phenylcarbamoyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide.

The title compound is prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amidehydrochloride and phenyl isocyanate in the presence of a tertiary aminebase such as N-methylmorpholine in a solvent such as methylene chloride.

Example 50 Morpholine-4-carboxylic Acid{1-[4-Cyano-1-(morpholine4-carbonyl)-piperidin-4-ylcarbamoyl-1-3,3-dimethyl-butyl]-amide

The title compound is prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amidehydrochloride and 4-morpholine carbonyl chloride in the presence of atertiary amine base such as N-methylmorpholine in a solvent such asmethylene chloride.

Example 51 Morpholine-4-carboxylic Acid(1-{4-Cyano-1-[(pyridin-3-ylmethyl)-carbamoyl]-piperidin-4-ylcarbamoyl}-3,3-dimethyl-butyl)-amide

The title compound is prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amidehydrochloride and 3-pyridyl-methyl isocyanate in the presence of atertiary amine base such as N-methylmorpholine in a solvent such asmethylene chloride.

Example 52 Morpholine-4-carboxylic Acid1-[4-Cyano-1-(4-methyl-piperazine-1-carbon1-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide.

The title compound is prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidehydrochloride and 4-methyl-piperzine carbonyl chloride in the presenceof a tertiary amine base such as N-methylmorpholine in a solvent such asmethylene chloride.

Example 534-(4-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidin-1-yl)-butyricAcid

The title compound is prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidehydrochloride and 4-bromo-butyric acid in the presence of a hinderedtertiary amine base such as Hunig's base in a solvent such as methylenechloride.

Example 54 Morpholine-4-carboxylic Acid[1-(4-Cyano-1-cyclopropyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide.

The title compound may be prepared from morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidehydrochloride and 1-ethoxy-1-trimethylsilyloxy-cyclopropane using areducing agent such sodium cyanoborohydride in a solvent system such asacetic acid in methanol.

Example 55 Morpholine-4-carboxylic Acid{1-[4-Cyano-1-(2-dimethylamino-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide.

The title compound is prepared by the method of Example 33.

Example 56 Morpholine-4-carboxylic Acid[1-(4-Cyano-1-phenyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

The title compound is prepared by a method analogous to that of Example58.

Example 57 Morpholine-4-carboxylic Acid{1-[4-Cyano-1-(1,1-dimethyl-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

The title compound can be prepared by a method analogous to that of themethod of Example 59.

Example 58 Morpholine-4-carboxylic Acid[1-(4-Cyano-1-phenyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide.

(a) N-Phenyl-4-piperidone.

1,4-Dioxa-8-azaspiro[4,5]-decane (2.0 g, 14.0 mmol, 1.0 equiv),Pd₂(DBA)₃ (0.31 g, 0.34 mmol, 0.024 equiv), BINAP (0.64 g, 1.0 mmol,0.073 equiv), NaO-t-Bu (3.9 g, 41 mmol, 3.0 equiv) and bromobenzene (2.6g, 17.7 mmol, 1.3 equiv) were combined under Ar in 50 mL of dry toluene.The resulting mixture was refluxed under Ar for 4 h. The reaction mixwas cooled and poured into 250 mL of saturated sodium bicarbonatesolution. The product was extracted with 3×100 mL CH₂Cl₂. The organicextracts were combined and concentrated. The product was purified byflash chromatography on SiO₂ using 50% hexanes in CH₂Cl₂ to pure CH₂Cl₂to give the N-phenyl ketal (2.9 g). The purified ketal was dissolved inmixture of 50 mL 1,4-dioxane, 50 mL water, and 20 mL concentrated HCl.The mixture was refluxed for 3 h at which time mass spectrometry showeddisapearance of the starting ketal. The cooled mixture was carefullypoured into 600 mL of saturated sodium bicarbonate solution and theproduct extracted with 3×200 mL EtOAc. The combined organic extractswere combined and dried over Na₂SO₄, decanted and concentrated to a redoil (2.3 g) which was used without further purification; MS, m/z176=M+1.

(b) 4-Amino-4-cyano-1-phenyl-piperidine.

N-Phenyl-4-piperidone (2.3 g, 13 mmol, 1.0 equiv) was dissolved in 26 mLof 2 M NH₃ in MeOH and NaCN (0.76 g, 15 mmol, 1.2 equiv) and NH₄Cl (0.80g, 15 mmol, 1.2 equiv) were added and the mixture was refluxed for 2 hat which time an additional 26 mL of 2 M NH₃/MeOH was added followed byanother 2 h of reflux. The reaction mixture was cooled and filtered. Thefiltrate was concentrated. The crude product was purified by flashchromatography on SiO₂ eluting with 100% CH₂Cl₂ and 2% MeOH in CH₂Cl₂ togive the pure product (1.92 g) as a thick yellow oil which solidified onstanding; MS, m/z 202=M+1.

(c) Morpholine-4-carboxylic Acid[1-(4-Cyano-1-phenyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide.

N-(4-morpholinecarbonyl)-L-neopenylglycine (0.2 g, 0.97 mmol, 1.0 equiv)and EDC (0.19 g, 0.97 mmol, 1.0 equiv) were combined in 10 mL of CH₂Cl₂and stirred for 15 min at room temperature. A solution of4-amino-4-cyano-1-phenyl-piperidine (0.20 g, 0.97 mmol, 1.0 equiv) in 5mL of CH₂Cl₂ and N-methyl-morpholine (0.31 g, 3.1 mmol, 4.0 equiv) wereadded and stirring was continued for 16 h. The reaction was concentratedin vacuo and the residue was triturated with 100 mL saturated sodiumbicarbonate solution with rapid stirring for 2 h. The resulting solidwas collected by filtration and recrystallized from CH₃CN and water (2to 1) to yield the title compound as an off-white solid (165 mg, 39%);MS, m/z 443=M+1.

Following the above procedures the following compounds can besynthesized:

Morpholine-4-carboxylic acid{1-[4-cyano-1-(2-methoxy-phenyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(3-methoxy-phenyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(4-methoxy-phenyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(2-methyl-phenyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(3-methyl-phenyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(4-methyl-phenyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(2-phenyl-phenyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(3-phenyl-phenyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(4-phenyl-phenyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(2-methoxy-phenyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(3-methoxy-phenyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(4-methoxy-phenyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(2-methyl-phenyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(3-methyl-phenyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(4-methyl-phenyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(2-phenyl-phenyl)-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(3-phenyl-phenyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(4-phenyl-phenyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Example 59 Morpholine-4-carboxylic Acid[1-(1-tert-Butyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide,

(a) N-Methoxy-N-methyl-acrylamide.

Acrolyl chloride (20 g, 221 mmol, 1.0 equiv) was dissolved n 500 mL ofCH₂Cl₂ and cooled to 0° C. Solid N,O-dimethyl-hydroxylaminehydrochloride (21.5 g, 221 mmol, 1.0 e quiv) was added all at once. Et₃Nwas added dropwise over a 2 h period to give a thick yellow mixture. Thereaction was stirred for an additional hour during which time it wasallowed to warm to room temperature. The mixture was poured into 1 L ofwater. Layers were separated and the organic layer was washed with 1×500mL water, 1×500 mL brine and dried over Na₂SO₄. The solution wasdecanted and concentrated in vacuo to give the desired product as ayellow oil (23 g, 90%) which was used without further purification.

(b) 3-(t-Butyl-amino)-N-methoxy-N-methyl-propanamide.

N-Methoxy-N-methyl-acrylamide (5 g, 43.4 mmol, 1.0 equiv) was dissolvedin t-butylamine (3.36 g, 46 mmol, 1.06 equiv). The resulting solutionwas stirred at room temperature for 48 h. The excess primary amine wasremoved in vacuo and the crude product was purified by flashchromatography on silica using 100% CH₂Cl₂ to 2% MeOH in CH₂Cl₂ to givethe desired product as a light yellow oil (5.7 g, 70%); MS, m/z 189=M+1.

(c) 1-t-Butyl-4-piperidone.

3-(t-Butyl-amino)-N-methoxy-N-methyl-propanamide (5 g, 26.6 mmol, 1.0equiv) was dissolved in dry THF (50 mL) under Ar. The solution wascooled to −78° C. and a 1 M solution of vinylmagnesium bromide (66.5 mL,66.5 mmol, 2.5 equiv) was added drops over a 20 min period. The reactionwas then stirred at −78° C. for 30 min and at 0° C. for 30 min at whichtime the reaction solution was transferred via a double-ended cannulainto ice-cold saturated sodium bicarbonate solution under Ar. Themixture was stirred for 10 min and the crude product was extracted 2×150ML EtOAc. The organic extracts were combined and concentrated in vacuoto a red oil. Purification was done by flash chromatography on silicausing 100% CH₂Cl₂ through 4, 8, and 16% MeOH in CH₂Cl₂. The product wasisolated as an orange oil (1.3 g, 32%); MS, m/z 156=M+1.

(d) 4-Amino-1-t-butyl-4-cyano-piperidine.

1-t-Butyl-4-piperidone (1.3 g, 8.4 mmol, 1.0 equiv), NaCN (0.61 g, 12.6mmol, 1.5 equiv), and NH₄Cl (0.67 g, 12.6 mmol, 1.5 equiv) were combinedin 34 m]L of 2 M NH₃ in MeOH. The mixture was refluxed for 2 h at whichtime an additional 34 mL of 2 M NH₃ in MeOH was added followed byanother 2 h at reflux. The mixture was cooled and filtered. The filtratewas concentrated in vacuo and the residue was triturated with CH₂Cl₂ andfiltered again. The solution was concentrated to a thick red oil whichwas used without further purification; MS, m/z 182=M+1.

(e) Morpholine-4-carboxylic Acid[1-(1-tert-butyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide.

N-(4-morpholinecarbonyl)-L-neopenylglycine (0.070 g, 0.27 mmol, 1.0equiv) and EDC (0.057 g, 0.30 mmol, 1.1 equiv) were combined in 10 mL ofDMF and stirred for 15 min at room temperature. A solution of4-amino-1-t-butyl-4-cyano-piperidine (0.054 g, 0.30 mmol, 1.1 equiv) in5 mL of DMF and N-methyl-morpholine (0.11 g, 1.1 mmol, 4.0 equiv) wereadded and stirring was continued for 16 h. The reaction was diluted with50 mL of saturated sodium bicarbonate solution and the product wasextracted with 3×50 mL EtOAc. The organic extracts were combined andconcentrated in vacuo. The product was purified by semi-prepreverse-phase HPLC using 20 to 60% CH₃CN in water over a 25 min gradientto yield the title compound as a white solid after concentration (25 mg,22%); MS, m/z 422=M+1.

Example 60 Morpholine-4-carboxylic Acid[1-(4-Cyano-1,2-dimethyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

(a) 3-(Benzyl-methyl-amino)-butyric Acid Methyl Ester.

Benzyl-methyl-amine (20 g, 165 mmol, 1.0 equiv) was added neat to methylcrotonate (19.8 g, 198 mmol, 1.2 equiv). The resulting solution wasstirred at room temperature for 72 h. The excess crotonic ester wasremoved in vacuo to yield the desired product (40.3 g, ˜100%) which wasused without further purification; MS, m/z 222=M+1.

(b) 3-Methylamino-butyric Acid Methyl Ester.

3-(Benzyl-methyl-amino)-butyric acid methyl ester (15 g, 67.8 mmol, 1.0equiv) was placed in a Parr hydrogenation bottle and dissolved in 50 mLof MeOH. 20% Palladium hydroxide on carbon (0.5 g, 0.94 mmol, 0.014equiv) was added and the mixture was shaken at 50 psi H₂ for 16 h. Thereaction was judged as complete when the uptake of H₂ had stopped. Thebottle was opened and 10 g of diatomaceous earth in 100 mL of MeOH wasadded. The mixture was filtered on a pad of diatomaceous earth which wasthen washed with 2×100 mL of MeOH. The filtrates were combined andconcentrated in vacuo to yield the desired product as an oil that issomewhat volatile (7.6 g, 85%). The crude product was used withoutfurther purification; MS, m/z 132=M+1.

(c) 3-[(2-Methoxycarbonyl-ethyl)-methyl-amino]-butyric Acid MethylEster.

3-Methylamino-butyric acid methyl ester (7.6 g, 58 mmol, 1.0 equiv) wasadded neat to methyl acrylate (7.5 g, 87 mmol, 1.5 equiv). The resultingsolution was refluxed for 16 h. The reaction was cooled and diluted withhexanes (200 mL) and an insoluble polymer separated out. The hexanesolution was decanted and the polymer washed 2×100 mL hexanes withvigorous stirring. The combined hexane solutions were then concentratedin vacuo. The crude product was purified by flash chromatography on SiO₂using pure CH₂Cl₂ as an eluent. The pure product was isolated as a clearcolorless oil (7.3 g, 58%); MS, m/z 218=M+1.

(d) 1,2-Dimethyl-4-piperidone.

A 1 M solution of TiCl₄ in CH₂Cl₂ (23 mL, 23 mmol, 1.0 equiv) was addedto a flask under Ar and cooled to −15° C. with a MeOH/ice water bath.3-[(2-Methoxycarbonyl-ethyl)-methyl-amino]-butyric acid methyl ester (5g, 23 mmol, 1.0 equiv) was added dropwise over a 25 min period as asolution in 75 mL of dry CH₂Cl₂ to give a dark red mixture that wasdifficult to stir with a magnetic stir bar. Stirring was continued anadditional 1 h and then Et₃N (5.1 g, 50.6 mmol, 2.2 equiv) was addeddropwise over a 30 min period and then the reaction was stirred anadditional 1.5 h at −15° C. The reaction mix was poured into 150 mL ofbrine and 150 mL of CH₂Cl₂ was added. After thorough mixing, the pH ofthe water was brought to 8-9 with Et₃N. The mix was filtered and thegel-like solid was washed 3×100 mL CH₂Cl₂. The filtrate layers wereseparated and the aqueous layer was washed 3×50 mL CH₂Cl₂. All of theorganic layers were combined and concentrated to a thick red oil. Theresidue was taken up in 150 mL of concentrated HCl and the solution wasrefluxed 4 h. The cooled reaction solution was evaporated to dryness andthe residue was dissolved in 200 mL of saturated sodium bicarbonatesolution. The product ketone was extracted with 2×100 mL of EtOAc. Theorganic layers were combined and dried over Na₂SO₄. The product waspurified by flash chromatography on SiO₂ using pure CH₂Cl₂ to 4% MeOH inCH₂Cl₂ as eluent. The product was isolated as an orange oil (1.23 g,42%); MS, m/z 128=M+1.

(e) 4-Amino-4-cyano-1,2-dimethyl-piperidine.

1,2-Dimethyl-4-piperidone (1.23 g, 9.67 mmol, 1.0 equiv) was dissolvedin 39 mL of 2 M NH₃ in MeOH (8 equiv NH₃). To this solution was addedNaCN (0.52 g, 10.6 mmol, 1.1 equiv) and NH₄Cl (0.57 g, 10.6 mmol, 1.1equiv). The resulting mixture was refluxed for 2 h at which time anadditional 39 mL of 2 M NH₃ in MeOH was added followed by an additional2 h of reflux. The reaction was cooled and filtered. The filtrate wasconcentrated and taken up in 100 mL of CH₂Cl₂ giving more saltprecipitate which was removed by a second filtration. The filtrate wasthen concentrated to thick orange oil (1.32 g, 89%). ¹H NMR showed a 3to 1 mixture of diastereomers of unknown configuration. The crudeproduct was used without further purification; MS, m/z 154=M+1.

(f) Morpholine-4-carboxylic Acid[1-(4-Cyano-1,2-dimethyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide.

N-(4-morpholinecarbonyl)-L-neopenylglycine (0.20 g, 0.77 mmol, 1.0equiv) and EDC (0.15 g, 0.77 mmol, 1.0 equiv) were combined in 10 mL ofDMF and stirred for 15 min at room temperature. A solution of4-amino-4-cyano-1,2-dimethyl-piperidine (0.11 g, 0.74 mmol, 0.95 equiv)in 5 mL of DMF and N-methyl-morpholine (0.31 g, 3.1 mmol, 4.0 equiv)were added and stirring was continued for 16 h. The reaction was dilutedwith 50 mL of saturated sodium bicarbonate solution and the product wasextracted with 3×50 mL of EtOAc. The organic layers were combined andconcentrated. The crude product was purified by semi-prep reverse-phaseHPLC using 20% CH₃CN in water to 60% CH₃CN in water over a gradient of16 min to give two peaks (diastereomers) eluting at 13.1 and 14.0 min(49 mg and 20 mg respectively); MS, m/z 394=M+1 for each peak.

Following the above procedures the following compounds can besynthesised:

Morpholine-4-carboxylic acid[1-(4-cyano-2-methyl-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-2-ethyl-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1,2-dipropyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(2-butyl-4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(2-benzyl-4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-2-cyclohexyl-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-2-cyclohexylmethyl-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-2-methyl-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-2-ethyl-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1,2-dipropyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(2-butyl-4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(2-benzyl-4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-2-cyclohexyl-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-2-cyclohexylmethyl-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Example 61 Morpholine-4-carboxylic Acid[1-(4-Cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

(a) 4-Amino-4-cyano-piperidine-1-carboxylic Acid t-Butyl Ester.

t-Butyl 4-oxo-1-piperidine-carboxylate (10 g, 50 mmol, 1.0 equiv) wasdissolved 100 mL of 2 M NH₃ in MeOH. NaCN (2.7 g, 55 mmol, 1.1 equiv)and NH₄Cl (3 g, 55 mmol, 1.1 equiv) were added and the resulting mixturewas refluxed for 2 h at which time an additional 100 mL of 2 M NH₃ inMeOH was added followed by another 2 h of reflux.

The reaction mixture was cooled and filtered. The MeOH was removed invacuo and the residue triturated with 100 mL of CH₂Cl₂ and filteredagain. The filtrate was concentrated by about 75% and 200 mL of hexaneswas added to give a tan precipitate that was collected by filtration toyield, after drying under vacuum, the desired product as cream-coloredsolid (10.1 g) which was used without further purification.

(b)4-Cyano-4-{3,3-dimethyl-2-[(morpholine-4-carbonyl)-amino]-pentanoylamino}-piperidine-1-carboxylicAcid t-Butyl Ester.

N-(4-morpholinecarbonyl)-L-neopenylglycine (1.00 g, 3.87 mmol, 1.00equiv) and EDC (0.739 g, 3.87 mmol, 1.00 equiv) were mixed in 20 mL ofCH₂Cl₂ and stirred for 15 min. A solution of4-amino-4-cyano-piperidine-1-carboxylic acid t-butyl ester (0.872 g,3.87 mmol, 1.00 equiv) in 10 mL CH₂Cl₂ and N-methyl-morpholine (1.56 g,15.5 mmol, 4.0 equiv) were added and the resulting solution was stirredat room temperature for 16 h. The reaction was diluted with 100 mLCH₂Cl₂ and 100 mL saturated sodium bicarbonate solution. The layers wereseparated and the aqueous was washed 2×50 mL CH₂Cl₂. The organicextracts were combined and dried over Na₂SO₄. The solution was decantedand concentrated to a white solid. The solid was dissolved in 20 mL ofCH₃CN and water (100 mL) was added to precipitate the product. Thefluffy white solid was collected by filtration and dried under highvacuum to yield the desired compound as a white powder (1.51 g).

(c) Morpholine-4-carboxylic Acid[1-(4-Cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amideHydrochloride.

4-Cyano-4-{3,3-dimethyl-2-[(morpholine-4-carbonyl)-amino]-pentanoylamino}-piperidine-1-carboxylicacid t-butyl ester (1.51 g, 3.24 mmol, 1.0 equiv) was dissolved in 50 mLof dry Et₂O under Ar. 4 M HCl in 1,4-dioxane (16 mL, 20 equiv) was addedand the mixture was stirred for 20 min. A white solid precipitatedalmost immediately upon addition of the acid. The mixture was filteredunder Ar and the solid was washed 2×25 mL of dry Et₂O. The solid wasdried under high vacuum to a bright white powder (1.25 g, 96%) which wasused without further purification.

(d) Morpholine-4-carboxylic Acid[1-(4-Cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide.

Morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amidehydrochloride (0.050 g, 0.12 mmol, 1.0 equiv), cyclohexanone (0.015 g,0.15 mmol, 1.2 equiv), and Na(OAc)₃BH (0.046 g, 0.22 mmol, 1.75 equiv)were mixed in 15 mL of 1% AcOH in THF. The reaction was stirred at roomtemperature for 16 h. The reaction was diluted with 25 mL of saturatedsodium bicarbonate solution and the product was extracted 4×25 mL EtOAc.The organic extracts were combined and concentrated. The crude productwas purified by semi-prep reverse-phase HPLC using 20 to 80% CH₃CN inwater over a gradient of 25 min to yield the desired product, pure, as awhite solid (0.012 g, 21%); MS, m/z 448=M+1.

Following the above procedures the following compound was synthesised:

Morpholine-4-carboxylic acid{1-[4-cyano-1-(tetrahydro-pyran-4-yl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide;MS, m/z 450=M+1

Following the above procedures the following compounds can besynthesized;

Morpholine-4-carboxylic acid[1-(1-butyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1-pentyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1-hexyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(1-ethyl-propyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(2-methyl-cyclohexyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(3-methyl-cyclohexyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(4-methyl-cyclohexyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(2-phenyl-cyclohexyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(3-phenyl-cyclohexyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(4-phenyl-cyclohexyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(cyclohexyl-methyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(cyclopropyl-methyl)-piperidin-4-ylcarbamoyl]-3,3-dimethyl-butyl}-amide

Morpholine-4-carboxylic acid[1-(1-butyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1-pentyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1-hexyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(1-ethyl-propyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(2-methyl-cyclohexyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(3-methyl-cyclohexyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(4-methyl-cyclohexyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(2-phenyl-cyclohexyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(3-phenyl-cyclohexyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(cyclopropyl-methyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(4-phenyl-cyclohexyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Morpholine-4-carboxylic acid{1-[4-cyano-1-(cyclohexyl-methyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Example 62 Morpholine-4-carboxylic Acid[1-(3-Cyano-1-cyclopropylmethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) 1-Cyclopropylmethyl-3-hydroxy-pyrrolidine.

3-Hydroxy-pyrrolidine (5.65 g, 65 mmol, 1.0 equiv) was dissolved in 100mL of 1% AcOH in THF and cooled to 0° C. Na(OAc)₃BH (24 g, 114 mmol,1.75 equiv) and cyclopropylcarboxaldehyde (5.0 g, 71 mmol, 1.1 equiv)were added and the resulting mixture was stirred at 0° C. for 1 h androom temperature overnight (16 h). The reaction was diluted with 200 mLof 2 N NaOH, and the product was extracted 3×200 mL of CH₂Cl₂. Theorganic extracts were combined, dried over Na₂SO₄, decanted andconcentrated to yield the desired product as a free-flowing oil (7.26 g,79%) which was used without further purification; MS, m/z 142=M+1.

(b) 1-Cyclopropylmethyl-pyrrolidin-3-one.

A solution of oxalyl chloride (13.1 g, 103 mmol, 2.0 equiv) was preparedin 200 mL of dry CH₂Cl₂ and cooled under Ar to −78° C. DMSO (16.1 g, 206mmol, 4.0 equiv) was added as a solution in 20 mL of CH₂Cl₂ dropwiseover a 30 min period giving vigorous gas formation. After addition, themixture was stirred for an additional 15 min and then a solution of1-cyclopropylmethyl-3-hydroxy-pyrrolidine (7.26 g, 52 mmol, 1.0 equiv)in 50 mL of CH₂Cl₂ was added dropwise over a 30 min period. Aftercomplete addition the reaction was stirred an additional a hour at −78°C. Et₃N (31 g, 309 mmol, 6.0 equiv) was added over a period of 10 min.The cold-bath was removed and the mixture was stirred while warming for1 h. The mixture was diluted with 500 mL of water and 100 mL of CH₂Cl₂.After thorough mixing, the layers were separated and the organic layerwas washed with 200 mL of water, dried over Na₂SO₄, decanted, andconcentrated to a yellow oil (6.1 g, 85%) which was used without furtherpurification.

c) 3-Amino-3-cyano-1-cyclopropyl-pyrrolidine.

1-Cyclopropylmethyl-pyrrolidin-3-one (6.1 g, 44 mmol, 1.0 equiv), NaCN(2.4 g, 48 mmol, 1.1 equiv) and NH₄Cl (2.6 g, 48 mmol, 1.1 equiv) weremixed in 88 mL of 2 M NH₃ in MeOH, and the resulting mixture wasrefluxed for 2 h at which time another 88 mL of 2 M NH₃ in MeOH wasadded followed by another 2 h at reflux. The reaction mixture wascooled, filtered, concentrated, and taken up in 100 mL of CH₂Cl₂. Themixture was filtered a second time and concentrated to a red oil (5.9 g)which was used without further purification.

(d) Morpholine-4-carboxylic Acid[1-(3-Cyano-1-cyclopropylmethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide.

N-(4-morpholinecarbonyl)-L-cyclohexyl alanine (1.00 g, 3.52 mmol, 1.00equiv) and EDC (1.01 g, 4.58 mmol, 1.30 equiv), and HoBt (0.72 g, 4.58mmol, 1.30 equiv) were mixed 20 mL of DMF for 15 min followed byaddition of 3-amino-3-cyano-1-cyclopropyl-pyrrolidine (0.86 g, 5.28mmol, 1.5 equiv) and N-methyl-morpholine (1.42 g, 14.1 mmol, 4.0 equiv).The resulting solution was stirred at room temperature for 16 h. Thereaction solution was diluted with 100 mL saturated sodium bicarbonatesolution and the product was extracted with 2×100 mL EtOAc. The organicextracts were combined and concentrated. The crude product was purifiedby semi-prep reverse-phase HPLC using 40 to 90% CH₃CN in water over agradient time of 30 min to give the desired product in two peaks(diastereomers) eluting at 9.5 min and 10.3 min respectively (128 mg and98 mg, 15% total purified yield); MS, m/z 432=M+1 for both peaks.

Following the above procedures the following compounds were alsoprepared:

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2-chloro-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 502=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(cyclohexyl-methyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 474=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-methyl-ethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amideMS, m/z 420=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(3-benzyloxy-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 574=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2-benzyloxy-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 574=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(3,5-difluoro-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 504=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2,6-difluoro-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 504=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(3-trifluoromethyl-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 536=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(3-phenoxy-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 560=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;MS, m/z 460=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-methyl-piperidine-4-yl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 475=M+1

Morpholine-4-carboxylic acid {l-[3-cyano-1-(3-methyl-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 482=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2-phenoxy-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 560=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(4-fluoro-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 486=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(2,4,6-trimethyl-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 510=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1H-indol-3-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 507=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopropyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;MS, m/z 418=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-pyridin-3-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 469=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;MS, m/z 448=M+1

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-2-hydroxymethyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;MS, m/z 472=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-isobutyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;MS, m/z 434=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-isopropyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;MS, m/z 394=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-isobutyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;MS, m/z 408=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 448=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butyl}-amide;MS, m/z 422=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-phenethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;MS, m/z 482=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-methyl-piperidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;MS, m/z 406=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;MS, m/z 394=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;MS, m/z 420=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(trans-4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 474=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(cis-4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 474=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopentyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;MS, m/z 420=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-isobutyl-piperidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;MS, m/z 448=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopentyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;MS, m/z 446=M+1

1-Benzyl-3-cyano-3-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-pyrrolidine-2-carboxylicacid methyl ester; MS, m/z 526=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(cis-4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butyl}-amide;MS, m/z 448=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(trans-4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butyl}-amide;MS, m/z 448=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexyl-pyrrolidin-3-ylcarbamoyl)-2-(4-iodo-phenyl)-ethyl]-amide;MS, m/z 580=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(3-methoxy-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 498=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(naphthalen-2-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 518=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopentylmethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;MS, m/z 460=M+1

Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;MS, m/z 434=M+1

[1-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-carbamicacid benzyl ester; MS, m/z 455=M+1

Example 63 Morpholine-4-carboxylic Acid(1-{3-Cyano-1-[1-(toluene-4-sulfonyl)-1H-indol-3-ylmethyl]-pyrrolidin-3-ylcarbamoyl}2-cyclohexyl-ethyl)-amide

(a)1-[1-(Toluene-4-sulfonyl)-1H-indol-3-ylmethyl]-3-hydroxy-pyrrolidine.

1-(Toluene-4-sulfonyl)-1H-indole-3-carboxaldehyde (prepared as describedin Chatterjee, R. K.; Indian J. Chem Sect. B 1994, 33(1), 32-37) wasreacted with 3-hydroxypyrrolidine as described forcyclopropylcarboxaldehyde in Example 60 part (a) to provide the desiredproduct.

(b) Morpholine-4-carboxylic Acid(1-{3-Cyano-1-[1-(toluene-4-sulfonyl)-1H-indol-3-ylmethyl]-pyrrolidin-3-ylcarbamoyl}-2-cyclohexyl-ethyl)-amide

The title compound was prepared from the product of part (a) andN-(4-morpholinecarbonyl)-L-cyclohexyl alanine by the procedure describedin Example 60; MS, m/z 661=M+1.

Example 64 Morpholine-4-carboxylic Acid{1-[4-Cyano-1-(1-methyl-piperidine-4-carbonyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

A solution of 1-methyl-piperidin-4-yl carboxylic acid (0.050 g, 0.30mmol, 1.0 equiv) and EDC (0.057 g, 0.30 mmol, 1.0 equiv) was prepared in15 mL of DMF. After 15 min morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidehydrochloride (0.128 g, 0.30 mmol, 1.0 equiv) was added followed byN-methyl-morpholine (0.12 g, 1.2 mmol, 4.0 equiv) followed by stirringovernight (16 h). The reaction mixture was diluted with 100 mL ofsaturated sodium bicarbonate solution and the product was extracted with2×50 mL of EtOAc. The combined organic extracts were concentrated. Thecrude product was purified by semi-prep reverse-phase HPLC using 20 to80% CH₃CN in water over a gradient of 25 min to yield the desiredproduct as a white solid (39 mg); MS, m/z 517=M+1.

Following the above procedure the following compound was alsosynthesized;

Morpholine-4-carboxylic acid{1-[4-cyano-1-(pyridine-4-carbonyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 497=M+1

Example 65N-[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-4-methanesulfonylamino-benzamide

(a) 4-Methanesulfonylamino-benzoic Acid.

Ethyl 4-amino-benzoate (5 g, 30 mmol, 1.0 equiv) was mixed in 50 mL ofCH₂Cl₂ with Et₃N (6.1 g, 60 mmol, 2.0 equiv). The solution was cooled to0° C. and methanesulfonyl chloride (3.8 g, 33 mmol. 1.1 equiv) was addedas a solution in 15 mL of CH₂Cl₂ dropwise over a 15 min period. Thereaction was stirred for 4 h at which time it was diluted with 50 mL ofwater. Layers were separated and the organic layer was washed with 50 mLof saturated sodium bicarbonate solution and concentrated. The resultingester was dissolved in 50 mL of MeOH and treated with 50 mL of 5 N NaOHfor 4 h. The reaction solution was extracted with Et₂O and the aqueouslayer was acidified to give a white precipitate that was collected byfiltration. The solid was dried and used without further purification.

(b)N-[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-4-methanesulfonylamino-benzamide.

This compound was prepared from the product of part (a) using theprocedure described in Example 24 to yield the desired product as awhite solid; MS, m/z 490=M+1.

Following the above procedures the following compounds were alsoprepared:

N-[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-4-methanesulfonylamino-benzamide;MS, m/z 526=M+1

N-[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-4-methanesulfonylamino-benzamide;MS, m/z 552=M+1

N-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-4-methanesulfonylamino-benzamide;MS, m/z 464=M+1

Example 66 Morpholine-4-carboxylic Acid[1-(1-Benzyl-3-cyano-1-oxy-pyrrolidin-3-ylcarbamoyl-2-cyclohexyl-ethyl]-amide

(a) Morpholine-4-carboxylic Acid[1-(1-Benzyl-3-cyano-1-oxy-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide.

Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide(0.50 g, 1.1 mmol, 1.0 equiv) was dissolved in CH₂Cl₂ (25 mL) and cooledto −78° C. under Ar. Solid K₂CO₃ (0.22 g, 1.7 mmol, 1.5 equiv) was addedfollowed by addition of solid m-CPBA (0.24 g, 1.1 mmol, 1.0 equiv). Theresulting mixture was stirred at −78° C. for 2 h and, then, allowed towarm to room temperature. The reaction mixture was filtered and thesolvent removed in vacuo. The residue was purified by flashchromatography on silica gel using 10-75% MeOH-EtOAc as a gradienteluent to give the desired product (0.32 g, 62%) as a white solid; MS,m/z 484=M+1.

Example 663-Cyano-3-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-pyrrolidine-1-carboxylicAcid Benzyl Ester

(a) 3-Hydroxy-pyrrolidine-1-carboxylic Acid Benzyl Ester.

3-Hydroxy-pyrrolidine (10 g, 115 mmol, 1.0 equiv) was dissolved in 2 NNaOH (100 mL) and the mixture was cooled to 0° C. Benzylchloroformate(21 g, 126 mmol, 1.1 equiv) was added dropwise over a 45 min period.After addition, the reaction was stirred at room temperature for 4 h atwhich time the pH was adjusted to 7-8 using concentrated HCl. Theproduct was extracted with 3×100 mL of CH₂Cl₂. The organic extracts werecombined and dried over Na₂SO₄, decanted and concentrated in vacuo toyield the desired product as a light yellow oil (24.1 g, 95%) that wasused without further purification.

(b) 3-Oxo-pyrrolidine-1-carboxylic Acid Benzyl Ester.

A solution of oxalyl chloride (12.6 g, 99 mmol, 2.0 equiv) was preparedin 250 mL of dry CH₂Cl₂ and cooled under Ar to −78° C. DMSO (15.5 g, 199mmol, 4.0 equiv) was added dropwise over a 15 min period giving vigorousgas formation. After addition, the mixture was stirred for an additional25 min and then a solution of 3-hydroxypyrrolidine-1-carboxylic acidbenzyl ester (11 g, 50 mmol, 1.0 equiv) in 20 mL of CH₂Cl₂ was addeddropwise over a 10 min period. After complete addition the reaction wasstirred an additional a hour at −78° C. Et₃N (55 mL, 398 mmol, 8.0equiv) was added over a period of 10 min. The cold-bath was removed andthe mixture was stirred while warming for 2 h. The mixture was dilutedwith 500 mL of water. After thorough mixing, the layers were separatedand the aqueous layer was extracted 2×150 mL of CH₂Cl₂. The combinedorganic layers were washed with 200 mL of sodium bicarbonate solutionand 200 mL of brine, dried over Na₂SO₄, decanted, and concentrated to ayellow oil. The product was purified by flash chromatography on silicagel using CH₂Cl₂ as eluent to yield the desired product as a colorlessoil (8.5 g).

(c) 3-Amino-3-cyano-pyrrolidine-1-carboxylic Acid Benzyl Ester.

3-Amino-3-cyano-pyrrolidine-1-carboxylic acid benzyl ester was preparedfrom the ketone from part (b) using the procedure described in Example 1part (a) to yield the desired product as a 2 to 1 to 1 mixture ofamino-nitrile, cyanohydrin and starting ketone that was used withoutfurther purification.

(d)3-Cyano-3-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-pyrrolidine-1-carboxylicAcid Benzyl Ester.

3-Cyano-3-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-pyrrolidine-1-carboxylicacid benzyl ester was prepared from the amine from part (c) using theprocedure described in Example 1 part (a) to yield after purification onsilica, the desired product as an off-white hard foam; MS, m/z 512=M+1.

Following the above procedures the following compound was alsosynthesized;

3-Cyano-3-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-pyrrolidine-1-carboxylicacid (2-propen-1-yl) ester; MS, m/z 462=M+1.

EXAMPLE 68 Morpholine-4-carboxylic Acid{1-[3-Cyano-1-(5,5-dimethyl-3-oxo-cyclohex-1-enyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

3-Cyano-3-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-pyrrolidine-1-carboxylicacid (2-propen-1-yl) ester (1.35 g, 2.93 mmol, 1.00 equiv) was dissolvedin 35 mL of CH₂Cl₂ along with dimedone (3.30 g, 23.5 mmol, 8.03 equiv).Pd(PPh₃)₄ (0.25 g, 0.22 mmol, 0.07 equiv) was added and the suspensionwas stirred at room temperature for 3.5 h. The reaction mixture wasconcentrated and taken up into EtOAc (100 mL) and extracted with 1 N HCl(2×50 mL). Concentration of the organic phase and purification of thecrude mixture by reverse-phase HPLC provide the product as two separatediastereomers; MS, m/z 500=M+1.

EXAMPLE 694-Cyano-4-{3-cyclohexyl-2-[(piperidine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicAcid Ethyl Ester

(a)4-Cyano-4-{3-cyclohexyl-2-[(1-t-butoxycarbonyl-piperidine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicAcid Ethyl Ester

This intermediate was prepared from 1-t-butoxycarbonyl-piperidinecarboxylic acid and4-cyano-4-{[3-cyclohexyl-2-amino]-propionylamino}-piperidine carboxylicacid ethyl ester hydrochloride using the procedure described in Example24.

(b)4-Cyano-4-{3-cyclohexyl-2-[(piperidine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicAcid Ethyl Ester.

The ester from (a) was dissolved in 10 mL of 4 N HCl in 1,4-dioxane at0° C. for 1 hour. The solution was concentrated in vacuo and the saltneutralized by sodium bicarbonate solution and the product extractedwith CH₂Cl₂. After concentration of the organic extract, the crudeproduct was purified by reverse-phase HPLC to yield the desired product;MS, m/z 462=M+1.

Following the above procedures the following compounds were alsosynthesized:

4-Cyano-4-{3-cyclohexyl-2-[(4-methyl-piperazine-1-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylicacid ethyl ester; MS, m/z 477=M+1.

4-Methyl-piperazine-1-carboxylic acid[1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]amide;MS, m/z 406=M+1.

EXAMPLE 70 Morpholine-4-carboxylic Acid[1-(1-Benzyl-3-cyano-azetidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

(a) 3-Amino-1-benzyl-3-cyano-azetidine.

1-Benzyl-3-oxo-azetidine (1.6 g, 10 mmol, 1.0 equiv), prepared asdescribed in the literature (Katritzky, A. R.; Cundy, D. J.; J.Heterocyclic Chem. 1994, 31 271-275), was dissolved in dry MeOH and thesolution was cooled to −78° C. Gaseous ammonia was was bubbled throughthe solution for 30 mins at which time 3 angstrom molecular sieves wereadded and the mixture transferred to a pressure tube. The solution washeated for 30 min at 60° C. The mixture was cooled to −78° C., the tubeopened and KCN (0.65 g, 10 mmol, 1.0 equiv) and NH₄Cl (0.27 g, 5 mmol,0.5 equiv) were added and the tube was resealed and heated at 60° C. for4 h. The reaction mixture was filtered and the filtrate was evaporated.The crude residue was purified by flash chromatography using 2% MeOH inCH₂Cl₂ to give the desired product (0.11 g, 6%) as a brown oil; MS, m/z188=M+1.

(b) Morpholine-4-carboxylic Acid[1-(1-Benzyl-3-cyano-azetidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide.

The title compound was prepared from 3-amino-1-benzyl-3-cyano-azetidineand N-(4-morpholinecarbonyl)-L-cyclohexyl alanine using to the proceduredescribed in Example 1 step (d) to yield the desired product as a whitesolid; MS, m/z 454=M+1.

EXAMPLE 71 Morpholine-4-carboxylic Acid[1-(3-Cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide

3-Cyano-3-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-pyrrolidine-1-carboxylicacid benzyl ester (0.1 g, 0.20 mmol, 1.0 equiv) was dissolved in 15 mLof absolute EtOH. 10% Pd on carbon (20 mg) was added and the mixture wasstirred under 1 atm of H₂ until the starting material disappeared by TLC(5% MeOH in CH₂Cl₂. The crude mixture was filtered on diatomaceous earthand the filtrate was concentrated. The crude material was purified byreverse-phase HPLC to give two diastereomers; MS, m/z 378=M+1.

EXAMPLE 72 Morpholine-4-carboxylic Acid{1-[3-Cyano-1-(2-methyl-2-phenyl-propyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide

Reductive amination of morpholine-4-carboxylic acid[1-(3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide with2,2-dimethyl-2-phenyl-acetaldehyde and Na(OAc)₃BH in 1% AcOH in THFprovided the desired product; MS, 510=M+1.

Following the above procedure the following compounds were alsosynthesized;

Morpholine-4-carboxylic acid{1-[3-cyano-1-(indan-2-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 508=M+1

Morpholine-4-carboxylic acid{1-[3-cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;MS, m/z 488=M+1.

EXAMPLE 72

2-{[Acetylimino-(4-methoxy-phenyl)-methyl]-amino}-N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide(Method E)

(a) N-(4-Methoxy-thiobenzoyl)acetamide.

A solution of acetyl chloride (4.69 g, 59.8 mmol) in acetone (20 mL) wasadded dropwise to a solution of 4-methoxythiobenzamide (5.00 g, 29.9mmol) and pyridine (4.76 g, 60.1 mmol) in acetone (30 mL). The reactionmixture was heated to reflux for 30 min then poured onto ice water. Theresulting precipitate was isolated via filtration and dried under vacuumovernight to provide a light yellow/orange solid (4.52 g, 72%). ¹H NMR(400 MHz, CDCl₃) δ 2.56 (s, 3H), 3.87 (s, 3H), 6.89 (dd, J=6.9, 2.0 Hz,2H), 7.77 (dd, J=6.9, 2.0 Hz, 2H).

(b)2-{[Acetylimino-(4-methoxy-phenyl)-methyl]-amino}-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide.

2-Chloro-N-methylpyridinium iodide (660 mg, 2.58 mmol), was added to asolution of N-(4-methoxy-thiobenzoyl)acetamide (420 mg, 2.01 mmol),2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt (730 mg, 2.00 mmol), andN,N-diisopropylethylamine (1.05 mL, 6.02 mmol) in dichloromethane (8.0mL). The reaction mixture was stirred at room temperature for 2 h, thendiluted with dichloromethane (100 mL)and washed with 2×150 mL ofsaturated sodium bicarbonate. The organic phase was dried (MgSO₄) andconcentrated. The resulting residue was chromatographed over 100 g offlash silica first using EtOAc, then dichloromethane/methanol 9:1 as theeluant to provide the desired product as an off white solid (377 mg,40%). ¹H NMR (400 MHz, DMSO-d6) δ 0.70-0.90 (m, 2H), 1.00-1.30 (m, 4H),1.35-1.65 (m, 8H), 1.72 (s, 3H), 1.85-2.20 (m, 6H), 2.48-2.60 (m, 1H),3.78 (s, 3H), 4.20-4.35 (m, 1H), 6.95-6.99 (m, 2H), 7.33 (d, J=8.4 Hz,1H), 7.72 (d, J=8.4 Hz, 1H). MS, m/z 468=M+1.

EXAMPLE 73

2-[(Acetylimino-phenyl-methyl)-amino]-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide

(a) Thiobenzoyl acetamide was prepared according to the procedure fromExample 1, step a, starting with thiobenzamide.

(b) The title compound was prepared starting from thiobenzoyl acetamideand2-amino-N-(4-cyano-l1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 72, stepb. MS, m/z 438=M+1.

EXAMPLE 74

2-{[Acetylimino-(4-fluoro-phenyl)-methyl]-amino}-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide

(a) N-(4-Fluoro-thiobenzoyl )acetamide was prepared according to theprocedure from Example 72, step a, starting with 4-fluorothiobenzamide.

(b) The title compound was prepared starting fromN-(4-fluoro-thiobenzoyl) acetamide and2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 72, stepb. MS, m/z 456=M+1.

EXAMPLE 75

2-[(Acetylimino-phenyl-methyl)]-amino]-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide

(a) The title compound was prepared starting from thiobenzoyl acetamideand2-amino-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 72, stepb, except that the compound was purified by HPLC using a 20×250 mm C18reverse phase column with the method being 20% acetonitrile in water to90% acetonitrile in water. MS, m/z 480=M+1.

EXAMPLE 76

{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylen}-carbamicAcid Ethyl Ester (Method E)

(a) (Morpholine-4-carbothioyl)-carbamic Acid Ethyl Ester.

Morpholine (7.5 mL, 86.0 mmol) was added dropwise to a solution of ethylisothiocyanato formate (10.0 mL, 84.8 mmol) in tetrahydrofuran (200 mL).The reaction mixture was stirred at room temperature for 2.5 h, thenconcentrated and dried under vacuum to provide the desired product as awhite solid (16.5 g, 89%). This material was used without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, J=7.1 Hz, 3H),3.61-3.97 (m, 8H), 4.16 (q, 7.1 Hz, 2H), 7.44 (br s, 1H).

(b){[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylen}-carbamicAcid Ethyl Ester.

2-Chloro-N-methylpyridinium iodide (680 mg, 2.66 mmol), was added to asolution of (Morpholine-4-carbothioyl)-carbamic acid ethyl ester (450mg, 2.06 mmol),2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt (745 mg, 2.04 mmol), andN,N-diisopropylethylamine (1.10 mL, 6.3 mmol) in dichloromethane (8.0mL). The reaction was stirred at room temperature for 2.5 h then takenup in 10% citric acid solution and washed with EtOAc. The aqueous phasewas then basified with saturated sodium carbonate and extracted withEtOAc. The organic extract was dried (MgSO₄) and concentrated to providethe desired product as a white solid (250 mg, 26%). This material wasfurther purified by HPLC using a 20×250 mm C₁₈ reverse phase column withthe method being 20% acetonitrile in water to 90% acetonitrile in water.MS, m/z 477=M+1.

EXAMPLE 77

{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicAcid Ethyl Ester

The title compound was prepared starting from(Morpholine-4-carbothioyl)-carbamic acid ethyl ester and2-amino-N-(-4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamidebis hydrochloride salt according to the procedure from Example 76, stepb, except that the compound was first purified by chromatography oversilica gel using 9:1 methylene chloride : methanol as the eluant priorto reverse phase HPLC purification. MS, m/z 505=M+1.

EXAMPLE 78

{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylimino]-morpholin-4-yl-methyl}-carbamicAcid Ethyl Ester

The title compound was prepared starting from(Morpholine-4-carbothioyl)-carbamic acid ethyl ester and2-amino-4,4-dimethyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride salt accordingto the procedure from Example 76. MS, m/z 460=M+1.

EXAMPLE 79

({1-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethylamino)}-morpholin-4-yl-methylene)-carbamicAcid Ethyl Ester

The title compound was prepared starting from(Morpholine-4-carbothioyl)-carbamic acid ethyl ester and2-amino-N-[3-cyano-1-(1ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide bishydrochloride salt according to the procedure from Example 76, step b, .MS, m/z 519=M+1.

EXAMPLE 80

N-(4-Cyano-l1-methyl-piperidin-4-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-phenyl-methyl)-amino]-propionamide(Method F)

(a) Benzimidic Acid Methyl Ester

Benzimidic acid methyl ester hydrochloride (5 g, 29.1 mmol) waspartitioned between saturated sodium carbonate solution (200 mL) anddiethyl ether (I100 mL). The organic layer was dried (MgSO₄) andconcentrated to provide the desired product as a colorless liquid (3.20g, 81%). This material was used without further purification. ¹H NMR(400 MHz, CDCl₃) δ 3.93 (s, 3H), 7.39-7.46 (m, 3H), 7.75 (d, J=1.1 Hz,2H).

(b) 1-Ethyl-3-(methoxy-phenyl-methylene)-urea.

A neat mixture of benzimidic acid methyl ester (750 mg, 5.56 mmol) andethyl isocyanate (808 mg, 11.3 mmol) was stirred at 50° C. for 24 h.Excess isocyanate was removed under vacuum to provide the desiredproduct as a colorless viscous oil (1.09 g, 95%). This material was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) 67 1.07 (t, J=7.3Hz, 3H), 3.25 (q, J=7.3 Hz, 2H), 3.87 (s, 3H), 4.97 (br s, 1H),7.36-7.40 (m, 2H), 7.45 (d, J=7.4 Hz, 1H), 7.69-7.71 (m, 2H). MS, m/z207=M+1.

(c)N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-phenyl-methyl)-amino]-propionamide.

A solution of 1-ethyl-3-(methoxy-phenyl-methylene)-urea (350 mg, 1.70mmol),2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt (512 mg, 1.40 mmol) and N,N-diisopropylethylamine(352 mg, 2.73 mmol) in dry methanol (5.0 mL) was stirred at roomtemperature for 60 h. The reaction mixture was concentrated and theresulting residue was chromatographed over 50 g of flash silica gelusing dichloromethane to 5% methanol in dichloromethane as the eluant.This provided the desired product as a light yellow solid (280 mg, 43%)which was further purified by HPLC using a 20×250 mm C₁₈ reverse phasecolumn with the method being 20% acetonitrile in water to 90%acetonitrile in water. MS, m/z 467=M+1.

EXAMPLE 81

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide(Method G)

(a) A suspension of 3-chloro-benzo[d]isothiazole 1,1-dioxide (300 mg,1.49 mmol) and2-amino-N-(-4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexylpropionamidebis hydrochloride salt (500 mg, 1.37 mmol) was prepared in 5.5 mL ofacetonitrile. Triethylamine (575 μL, 4.10 mmol) was added and thereaction mixture was stirred at room temperature for 1 day. Thesuspension was filtered to remove triethylamine hydrochloride and thefiltrate was concentrated. The resulting residue was chromatographedover 50 g of flash silica using dichloromethane/methanol 9:1 as theeluant to provide the desired product as a light yellow solid (310 mg,49%). ¹H NMR (400 MHz, CDCl₃) δ 0.25-0.45 (m, 1H), 0.65-0.85 (m, 2H),0.95-1.10 (m, 2H), 1.30-1.60 (m, 7H), 1.75-1.85 (m, 2H), 1.85-2.2 (m,2H), 2.31 (s, 3H), 2.35-2.50 (m, 3H), 2.65-2.80 (m, 2H), 4.60-4.70 (m,1H), 7.35-7.50 (m, 2H), 7.58 (t, J=7.3, 1H), 7.78 (d, J=7.7 Hz, 1H),7.81 (br s, 1H), 8.91 (br s, 1H). MS, m/z 458=M+1.

EXAMPLE 82

N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cuclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide

The title compound was prepared starting from3-chloro-benzo[d]isothiazole 1,1-dioxide and2-amino-N-(4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamide bishydrochloride salt according to the procedure from Example 81, exceptthat the compound was further purified by HPLC using a 20×250 mm C₁₈reverse phase column with the method being 20% acetonitrile in water toacetonitrile. MS, m/z 486=M+1.

EXAMPLE 83

2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoicAcid(4-Cyano-1-propylpiperidin-4-yl)-amide

The title compound was prepared starting from3-chloro-benzo[d]isothiazole 1,1-dioxide and2-amino-4,4-dimethyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride salt accordingto the procedure from Example 81, except that the compound was furtherpurified by HPLC using a 20×250 mm C₁₈ reverse phase column with themethod being 20% acetonitrile in water to acetonitrile. MS, m/z 460=M+1.

EXAMPLE 84

N-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide

The title compound was prepared starting from 3-chlorobenzo[d]isothiazole 1,1-dioxide and2-amino-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 81,except that the compound was further purified by HPLC using a 20×250 mmC₁₈ reverse phase column with the method being 40% acetonitrile in waterto acetonitrile. MS, m/z 500=M+1.

EXAMPLE 85

N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide

The title compound was prepared starting from 3-chlorobenzo[d]isothiazole 1,1-dioxide and2-amino-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 81,except that the compound was further purified by HPLC using a 20×250 mmC₁₈ reverse phase column with the method being 40% acetonitrile in waterto acetonitrile. MS, m/z 512=M+1.

EXAMPLE 86N-(4-Cyano-methyl-piperidin-4-yl)-3-cyclohexyl-2-(3-oxo-3H-isoindol-1-ylamino)-propionamide

The title compound was prepared starting from3-imino-2,3-dihydro-isoindol-1-oneand2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 81,except that refluxing THF was used as the solvent. The compound wasfurther purified by HPLC using a 20×250 mm C₁₈ reverse phase column withthe method being 20% acetonitrile in water to acetonitrile. MS, m/z422.5=M+1.

EXAMPLE 87

4,4-Dimethyl-2-(3-oxo-3H-isoindol-1-ylamino)-pentanoicacid-(4-cyano-1-propyl-piperidin-4-yl)-amide

The title compound was prepared from3-imino-2,3-dihydro-isoindol-1-oneand 2-amino-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride saltaccording to the procedure from Example 86. MS, m/z 424.5=M+1.

EXAMPLE 88

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(5,6-difluoro-3-oxo-3H-isoindol-1-ylamino)propionamide

(a) 2-Chloro-4,5-difluorobenzoic Acid Methyl Ester

2-Chloro-4,5-difluorobenzoic acid (1.93 g, 10 mmol) was dissolved in 20mL of acetone. Cesium carbonate (5.29 g, 15 mmol) was added followed byiodomethane (1.0 mL, 15 mmol). This reaction mixture was heated underreflux for 1 h and then cooled to room temperature. This suspension wasthen diluted with 40 mL of ethyl ether. The solid was removed byfiltration and washed with ethyl ether. The filtrate was evaporated invacuo to give the title compound in quantitative yield as a clear oil.

(b) 2-Cyano-4,5-difluorobenzoic Acid Methyl Ester

The above oil (2.06 g, 10 mmol) was dissolved in 10 mL of N-methylpyrrolidinone. Copper (I) cyanide (1.79 g, 20 mmol) was added. Thismixture was heated at 195° C. under nitrogen for 1 H. After cooling toroom temperature, this solution was diluted with 100 mL of water. Theresulting solid was collected by filtration. This solid was thensuspended in a rapidly stir-red solution of potassium cyanide (0.5 g) in30 mL of water for 1 H. EtOAc (30 mL) was added. The mixture wasfiltered through diatomaceous earth. The organic phase was separated andthe aqueous phase was extracted with EtOAc (20 mL×2). The combinedorganic phase was washed with brine and dried over magnesium sulfate.The solvent was removed in vacuo. The residue was crystallized fromethyl ether and petroleum ether to give the title compound as a yellowsolid (1.26 g, 64%).

(c) 5,6-Difluoro-2,3-dihydro-3-imino-1H-isoindol-1-one.

The above solid (0.493 g, 2.5 mmol) was dissolved in 20 mL of MeOH. Thissolution was saturated with ammonia at 0° C. and then stirred in apressure tube at room temperature for 3 days. The solid was collected byfiltration and washed with ethyl ether to give the title compound as ayellow solid (0.363 g, 80%).

The title compound was prepared from5,6-difluoro-2,3-dihydro-3-imino-1H-isoindol-1-one and2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 86. MS,m/z 458.3=M+1.

EXAMPLE 89

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide

The title compound was prepared starting from 4-chloro-benzo[e][1,3]oxazin-2-one (prepared from benzo [e][1,3] oxazin-2,4-dione and PCl₅ inrefluxing toluene) and2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 81. MS,m/z 438=M+1.

EXAMPLE 90

N-(4-Cyano-1-methyl-piperidin-4-yl)-2-(4-cyano-pyrimidin-2-ylamino)-3-cyclohexyl-propionamide(Method G)

2-Chloro-4-pyrimidinecarbonitrile (0.3 mmol, Daves, G. D. Jr., O'Brien,D. E., Cheng, C. C. J. Het. Chem, 1964, 1, 130) and2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide(0.7 mmol) were dissolved in acetonitrile (10 mL) containingN,N-diisopropylethylamine (0.6 mmol). The solution was heated to agentle reflux for 17 h. The volatiles were evaporated and the residuewas subjected to chromatography (silica gel, eluant=EtOAc then MeOH).The methanolic fraction was concentrated to a colorless solid which wasrechromatographed (10% MeOH/EtOAc) to afford the title compound as acolorless solid (52%). The material was recrystallized fromdichloromethane/petroleum ether.

EXAMPLE 91

N-(4-Cyano-1-methyl-piperidin-4-yl)-2-4-trifluoromethyl-pyrimidin-2-ylamino)-3-cyclohexyl-propionamide

The title compound was prepared from 2-chloro-4-trifluoromethylpyrimidine and2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamideaccording to the procedure from Example 90. MS, m/z 439.5=M+1.

EXAMPLE 92

N-(4-Cyano-1-methyl-piperidine-4-yl)-3-cyclohexyl-2[N-cyano-morpholine-4-carboximidoyl)-amino]-propionamide(Method H)

(a)2-(N-Cyano-iminomethylene-amino)-N-(4-cyano-1-methyl-piperidine-4-yl)-3-cyclohexyl-propionamide

A solution of diphenylcyanocarbonimidate (455 mg, 1.91 mmol),2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt (680 mg, 1.86 mmol) and N,N-diisopropylethylamine(482 mg, 3.73 mmol) in isopropanol (5.0 mL) was stirred overnight atroom temperature. The reaction mixture was then filtered to provide thedesired carbodiimide as a white powder (140 mg, 22%). This material wasused without further purification. ¹H NMR (400 MHz, CDCl₃) δ 0.80-1.00(m, 2H), 1.05-1.20 (m, 1H), 1.20-1.40 (2H), 1.50-1.85 (m, 8H), 2.32 (s,3H), 2.40-2.50 (m, 2H), 2.55-2.70 (m, 4H), 2.85-2.95 (m, 2H), 4.10-4.20(m, 1H), 8.77 (br s, 1H). MS, m/z 343=M+1.

(b)2-(N-Cyano-benzimidoyl-amino)-N-(4-cyano-1-methyl-piperidine-4-yl)-3-cyclohexyl-propionamide.

A suspension of2-(N-Cyano-iminomethylene-amino)-N-(4-cyano-1-methyl-piperidine-4-yl)-3-cyclohexyl-propionamide(120 mg, 0.35 mmol) in tetrahydrofuran (1 mL) was treated withmorpholine (4 mL, 45.9 mmol). The reaction mixture was stirred at roomtemperature for 3 days then concentrated to dryness. The residue waspurified by HPLC using a 20×250 mm C₁₈ reverse phase column with themethod being 20% acetonitrile in water to 90% acetonitrile in water. MS,m/z 430=M+1.

EXAMPLE 93

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-{[(diethyl-carbamoylimino)-morpholin-4-yl-methyl]-amino}-propionamide(Method H)

(a) N,N-Diethyl Carbamoyl Thiocyanate.

A suspension of sodium thiocyanate (3.30 g, 40.7 mmol) in dryacetonitrile (25 mL) at 80° C. was treated dropwise with a solution ofN,N-diethyl carbamoyl chloride (5.0 g, 36.9 mmol) in dry acetonitrile(15 mL). The reaction mixture was stirred at 80° C. for 50 min, cooledto room temperature, then filtered through a fine glass frit. Theresulting filtrate was used as a 0.9 M solution of N,N-diethyl carbamoylthiocyanate in acetonitrile.

(b)N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(3-diethylamino-carbonyl-thioureido)-propionamide

A solution of2-amino-N-(-4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamidebis hydrochloride salt (560 mg, 1.53 mmol) and triethylamine (500 μL,3.59 mmol) in acetonitrile (4 mL) was treated with a solution ofN,N-diethyl carbamoyl thiocyanate in acetonitrile (3.0 mL, 2.7 mmol).The reaction mixture was stirred overnight at room temperature andconcentrated on a rotary evaporator. The resulting residue waschromatographed (ethyl acetate: hexanes 1:1 then ethyl acetate andfinally methanol: methylene chloride 1:9 as the eluant) to provide thedesired product as a light yellow solid (340 mg, 49%). MS, m/z451.3=M+1.

The title compound was prepared by treating a solution of the resultingthiourea (340 mg, 0.75 mmol) and triethylamine (230 μL, 1.65 mmol) indry acetonitrile (4 mL) with mercury (II) chloride (225 mg, 0.83 mmol)and morpholine (200 μL, 2.23 mmol). The reaction mixture was stirred atroom temperature for 4 h then filtered through a 0.45 μm filter disc.The resulting filtrate was filtered through a column of silica (5%methanol/methylene chloride as the eluant) and the resulting crudeproduct was further purified by HPLC using a 20×250 mm C₁₈ reverse phasecolumn with the method being 20% acetonitrile in water to acetonitrile.MS, m/z 504.6=M+1.

The following examples were prepared by Method H in a parallel fashion:

EXAMPLE 94

{[1-(4-cyano-1methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-pyrrolidin-1-yl-methyl}-carbamicacid ethyl ester. MS, m/z 461=M+1.

EXAMPLE 95

{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-piperidin-yl-methyl}-carbamicacid ethyl ester. MS, m/z 477=M+1.

EXAMPLE 96

{Azepan-1-yl-[1-(4-cyano-1methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-methylene}-carbamicacid ethyl ester. MS, m/z 490=M+1.

EXAMPLE 97

{Azocan-1-yl-[1-(4-cyano-1methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-methylene}-carbamicacid ethyl ester. MS, m/z 504=M+1.

EXAMPLE 98

1-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-ethoxycarbonylimino-methyl}-piperidine-4-carboxylicacid ethyl ester. MS, m/z 548=M+1.

EXAMPLE 99

1-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-ethoxycarbonylimino-methyl}-piperidine-3-carboxylicacid ethyl ester. MS, m/z 548=M+1.

EXAMPLE 100

[[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methylene]-carbamicacid ethyl ester. MS, m/z 545=M+1.

EXAMPLE 101

{[1,4′]Bipiperidinyl-1′-yl-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-methylene}-carbamicacid ethyl ester. MS, m/z 559=M+1.

EXAMPLE 102

[[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-(4-phenyl-piperazin-1-yl)-methylene]-carbamicacid ethyl ester. MS, m/z 553=M+1.

EXAMPLE 103

[[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-(4-ethyl-piperazin-1-yl)-methylene]-carbamicacid ethyl ester. MS, m/z 505=M+1.

EXAMPLE 104

{(4-Acetyl-piperazin-1-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-methylene}-carbamicacid ethyl ester. MS, m/z 519=M+1.

EXAMPLE 105

4-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-ethoxycarbonylimino-methyl}-piperazine-1-carboxylicacid ethyl ester. MS, m/z 549=M+1.

EXAMPLE 106

[[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-(3,3,5-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methylene]-carbamicacid ethyl ester. MS, m/z 544=M+1.

The following examples may also be made by the methods described above:

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (4-cyano-1-methyl-piperidin-4-yl)-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (4-cyano-1-methyl-piperidin-4-yl)-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (4-cyano-1-methyl-piperidin-4-yl)-amide

{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-motpholin-4-yl-methylene}-carbamicacid ethyl ester

{[1-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-amide

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-amide

{[1-(3-Cyano-1-cyclohexyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

({1-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid [3-cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid [3-cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid [3-cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid [3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid [3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-amide

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid [3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-amide

({1-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester

({1-[3-Cyano-1-(1-H-indol-3-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid [3-cyano-1-(1-H-indol-3-ylmethyl)-pyrrolidin-3-yl]-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid [3-cyano-1-(1-H-indol-3-ylmethyl)-pyrrolidin-3-yl]-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid [3-cyano-1-(1-H-indol-3-ylmethyl)-pyrrolidin-3-yl]-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (1-benzyl-3-cyano-pyrrolidin-3-yl)-amide

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (1-benzyl-3-cyano-pyrrolidin-3-yl)-amide

{[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (1-benzyl-3-cyano-pyrrolidin-3-yl)-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (3-cyano-1-phenethyl-pyrrolidin-3-yl)-amide

{[1-(3-Cyano-1-phenethyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (3-cyano-1-phenethyl-pyrrolidin-3-yl)-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (3-cyano-1-phenethyl-pyrrolidin-3-yl)-amide

N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-propionamide

N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-propionamide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-N-(4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexyl-propionamide

N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-propionamide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-[(methanesulfonylimino-morpholin-4-yl-methyl)-amino]-propionamide

{[1-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

N-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-propionamide

N-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-3-cyclohexyl-2-[(methanesulfonylimino-morpholin-4-yl-methyl)-amino]-propionamide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-N-(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-3-cyclohexyl-propionamide

N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-2-[(methanesulfonylimino-morpholin-4-yl-methyl)-amino]-propionamide

N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-propionamide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-propionamide

{[1-(3-Cyano-1-cyclohexyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

({1-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester

N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-[(ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-propionamide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-N-[3-cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide

N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-[(methanesulfonylimino-morpholin-4-yl-methyl)-amino]-propionamide

N-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-[(methanesulfonylimino-morpholin-4-yl-methyl)-amino]-propionamide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide

N-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-[(ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-propionamide

({1-[3-Cyano-1-(1H-indol-3-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester

N-[3-Cyano-1-(-H-indol-3-ylmethyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-[(ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-propionamide

N-[3-Cyano-1-(1-H-indol-3-ylmethyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-[(methanesulfonylimino-morpholin-4-yl-methyl)-amino]-propionamide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-N-[3-cyano-1-(1H-indol-3-ylmethyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide

N-(1-Benzyl-3-cyano-pyolidin-3-yl)-2-[(carbamoylimino-morpholin-4-yl-methyl)-amino]-3-cyclohexyl-propionamide

N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-propionamide

{[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-3-cyclohexyl-2-[(methanesulfonylimino-morpholin-4-yl-methyl)-amino]-propionamide

N-(3-Cyano-1-phenethyl-pyrrolidin-3-yl)-3-cyclohexyl-2-[(methanesulfonylimino-morpholin-4-yl-methyl)-amino]-propionamide

{[1-(3-Cyano-1-phenethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

N-(3-Cyano-1-phenethyl-pyrrolidin-3-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-propionamide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-H-(3-cyano-1-phenethyl-pyrrolidin-3-yl)-3-cyclohexyl-propionamide

{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3-methyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid (4-cyano-1-cyclohexylmethyl-pyrrolidin-4-yl)-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid (4-cyano-1-methyl-piperidin-4-yl)-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoic acid(4-cyano-1-methyl-piperidin-4-yl)-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid (4-cyano-1-methyl-piperidin-4-yl)-amide

{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-3-methyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

{[1-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid (3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid (3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-amide

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoic acid(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-amide

{[1-(3-Cyano-1-cyclohexyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

({11-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-3-methyl-butylaminol}-morpholin-4-yl-methylene)-carbamicacid ethyl ester

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid [3-cyano-1-(4-methyl -cyclohexyl)-pyrrolidin-3-yl]-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoic acid[3-cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid [3-cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid [3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoic acid[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-amide

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid [3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-amide

({1-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-3-methyl-butylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester

({1-[3-Cyano-1-(1-H-indol-3-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-3-methyl-butylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid [3-cyano-1-(1-H-indol-3-ylmethyl)-pyrrolidin-3-yl]-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid [3-cyano-1-(1-H-indol-3-ylmethyl)-pyrrolidin-3-yl]-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoic acid[3-cyano-1-(1-H-indol-3-ylmethyl)-pyrrolidin-3-yl]-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoic acid(1-benzyl-3-cyano-pyrrolidin-3-yl)-amide

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid (1-benzyl-3-cyano-pyrrolidin-3-yl)-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoic acid(1-benzyl-3-cyano-pyrrolidin-3-yl)-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid (1-benzyl-3-cyano-pyrrolidin-3-yl)-amide

2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino-4-methyl-pentanoicacid (3-cyano-1-phenethyl-pyrrolidin-3-yl)-amide

{[1-(3-Cyano-1-phenethyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester

2-[(Ethylcarbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoicacid (3-cyano-1-phenethyl-pyrrolidin-3-yl)-amide

2-[(Carbamoylimino-morpholin-4-yl-methyl)-amino]-4-methyl-pentanoic acid(3-cyano-1-phenethyl-pyrrolidin-3-yl)-amide

{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-phenyl-methylene}-carbamicacid ethyl ester

2-[(Ethylcarbamoylimino-phenyl-methyl)-amino]-4-methyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

2-[(Methanesulfonylimino-phenyl-methyl)-amino]-4-methyl-pentanoic acid(3-propyl-piperidin-4-yl)-amide

2-[(Carbamoylimino-phenyl-methyl)-amino]-4,4-dimethyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

{[1-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butylamino]-piperazin-1-yl-methylene}-carbamic acid ethyl ester

2-[(Ethylcarbamoylimino-piperazin-1-yl-methyl)-amino]-4-methyl-pentanoicacid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

2-[(Methanesulfonylimino-piperazin-1-yl-methyl)-amino]-4-methyl-pentanoicacid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

2-[(Carbamoylimino-piperazin-1-yl-methyl)-amino]-4-methyl-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

({1-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethylamino}-pyridin-4-yl-methylene)-carbamicacid ethyl ester

N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-[(ethylcarbamoylimino-pyridin-4-yl-methyl)-amino]-propionamide

2-[(Carbamoylimino-pyridin-4-yl-methyl)-amino]-N-[3-cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide

N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-[(methanesulfonylimino-pyridin-4-yl-methyl)-amino]-propionamide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-pyrazin-2-yl-methyl)-amino]-propionamide

2-[(Carbamoylimino-pyrazin-2-yl-methyl)-amino]-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-[(methanesulfonylimino-pyrazin-2-yl-methyl)-amino]-propionamide

{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-pyrazin-2-yl-methylene}-carbamicacid ethyl ester

{[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-butylamino]-carbamoylimino-methyl}-carbamicacid benzyl ester

{[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-butylamino]-ethylcarbamoylimino-methyl}-carbamicacid benzyl ester

{[1-(1-Benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-butylamino]-methanesulfonylimino-methyl}-carbamicacid benzyl ester

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-methyl-piperidin-4-yl)-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoicacid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoicacid [3-cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoicacid [3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoicacid [3-cyano-1-(1H-indol-3-ylmethyl)-pyrrolidin-3-yl]-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoicacid (3-cyano-1-phenethyl-pyrrolidin-3-yl)-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoicacid (1-benzyl-3-cyano-pyrrolidin-3-yl)-amide

N-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide

N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide

N-[3-Cyano-1-(1H-indol-3-ylmethyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide

N-(3-Cyano-1-phenethyl-pyrrolidin-3-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide

N-(1-Benzyl-3-cyano-pyrrolidin-3-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4-methyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4-methyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4-methyl-pentanoicacid (3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4-methyl-pentanoicacid (3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4-methyl-pentanoicacid [3-cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4-methyl-pentanoicacid [3-cyano-1(1-ethyl-propyl)-pyrrolidin-3-yl]-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4-methyl-pentanoicacid [3-cyano-1-(1H-indol-3-ylmethyl)-pyrrolidin-3-yl]-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4-methyl-pentanoicacid (3-cyano-1-phenethyl-pyrrolidin-3-yl)-amide

2-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4-methyl-pentanoicacid (1-benzyl-3-cyano-pyrrolidin-3-yl)-amide

N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclohexyl-2-(3-oxo-3H-isoindol-1-ylamino)-propionamide

4-Methyl-2-(3-oxo-3H-isoindol-1-ylamino)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(3,4-dihydro-1H-pyrano[4,3-c]pyridin-5-ylamino)-propionamide

2-(3,4-Dihydro-1H-pyrano[4,3-c]pyridin-5-ylamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-methyl-piperidin-4-yl)-amide

2-(3,4-Dihydro-1H-pyrano[4,3-c]pyridin-5-ylamino)-4-methyl-pentanoicacid (4-cyano-1-methyl-piperidin-4-yl)-amide

N-(3-Cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-3-cyclohexyl-2-(isoquinolin-1-ylamino)-propionamide

2-(Isoquinolin-1-ylamino)-4,4-dimethyl-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

2-(Isoquinolin-1-ylamino)-4-methyl-pentanoic acid(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-yl)-amide

2-(Imidazo[1,5-a]pyridin-3-ylamino)-4-methyl-pentanoic acid(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-amide

2-(Imidazo[1,5-a]pyridin-3-ylamino)-4,4-dimethyl-pentanoic acid(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-amide

N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-2-(imidazo[1,5-a]pyridin-3-ylamino)-propionamide

N-[3-Cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-(8-oxo-8,9-dihydro-7H-purin-6-ylamino)-propionamide

4-Methyl-2-(8-oxo-8,9-dihydro-7H-purin-6-ylamino)-pentanoic acid[3-cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-amide

4,4-Dimethyl-2-(8-oxo-8,9-dihydro-7H-purin-6-ylamino)-pentanoic acid[3-cyano-1-(4-methyl-cyclohexyl)-pyrrolidin-3-yl]-amide

2-{1-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butylamino}-pyrimidine-4-carboxylicacid amide

2-{1-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-3-methyl-butylamino}-pyrimidine-4-carboxylicacid amide

2-{1-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethylamino}-pyrimidine-4-carboxylicacid amide

4-Methyl-2-(2-oxo-1,2-dihydro-quinazolin-4-ylamino)-pentanoic acid(3-cyano-1-cyclopentylmethyl-pyrrolidin-3-yl)-amide

N-(3-Cyano-1-cyclopentylmethyl-pyrrolidin-3-yl)-3-cyclohexyl-2-(2-oxo-1,2-dihydro-quinazolin-4-ylamino)-propionamide

4,4-Dimethyl-2-(2-oxo-1,2-dihydro-quinazolin-4-ylamino)-pentanoic acid(3-cyano-1-cyclopentylmethyl-pyrrolidin-3-yl)-amide

N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclohexyl-2-(4-oxo-3,4-dihydro-phthalazin-1-ylamino)-propionamide

4-Methyl-2-(4-oxo-3,4-dihydro-phthalazin-1-ylamino)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

4,4-Dimethyl-2-(4-oxo-3,4-dihydro-phthalazin-1-ylamino)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

2-(1H-Indazol-3-ylamino)-4-methyl-pentanoic acid(4-cyano-l1-methyl-piperidin-4-yl)-amide

2-(1H-Indazol-3-ylamino)-4,4-dimethyl-pentanoic acid(4-cyano-l1-propyl-piperidin-4-yl)-amide

N-[4-Cyano-1-(2-hydroxy-ethyl)-piperidin-4-yl]-3-cyclohexyl-2-(1H-indazol-3-ylamino)-propionamide

4-Methyl-2-(2-oxo-2H-benzo[e] [1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-piperidin-4-yl)-amide

4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

N-[4-Cyano-1-(2-hydroxy-ethyl)-piperidin-4-yl]-3-cyclohexyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide

2-(6-Hydroxy-1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methyleneamide

4-Methyl-piperazine-1-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methyleneamide

4,4-Dimethyl-2-{[morpholin-4-yl-(2-morpholin-4-yl-ethylcarbamoylimino)-methyl]-amino}-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-{[N-(5-methyl-oxazol-2-yl)-morpholine-4-carboximidoyl]-amino}-propionamide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-{[N-(1-methyl-1H-imidazol-2-yl)-morpholine-4-carboximidoyl]-amino}-propionamide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-{[N-(2-methyl-2H-[1,2,4]triazol-3-yl)-morpholine-4-carboximidoyl]-amino}-propionamide

[[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-methylene]-carbamicacid ethyl ester

[[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-(2-methoxymethyl-morpholin-4-yl)-methylene]-carbamicacid ethyl ester

[[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-(2,6-dimethyl-morpholin-4-yl)-methylene]-carbamicacid ethyl ester

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-{[-(4-methoxy-phenyl)-mopholine-4-carboximidoyl]-amino}-propionamide

4-({N-[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-morpholine-4-carboximidoyl}-amino)-benzamide

2-({N-[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-morpholine-4-carboximidoyl})-amino-oxazole-5-carboxylicacid amide

2-({N-[-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-morpholine-4-carboximidoyl}-amino)-oxazole-4-carboxylicacid amide

5-({N-[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-morpholine-4-carboximidoyl}-amino)-pyridine-2-carboxylicacid amide

2-({N-[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-morpholine-4-carboximidoyl}-amino)-3H-imidazole-4-carboxylicacid amide

2-[(N-Benzooxazol-2-yl-morpholine-4-carboximidoyl)-amino]-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-[(thiazol-2-yl-morpholine-4-carboximidoyl)-amino]-propionamide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-{[N-(5-phenyl-thiazol-2-yl)-morpholine-4-carboximidoyl]-amino}-propionamide

2-{[N-(5-Carbamoylmethyl-oxazol-2-yl)-morpholine-4-carboximidoyl]-amino}-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-{[N-(2-methyl-oxazol-5-yl)-morpholine-4-carboximidoyl]-amino}-propionamide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-3-ylamino)-propionamide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazin-3-ylamino)-propionamide

[[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-(2-methylcarbamoyl-morpholin-4-yl)-methylene]-carbamicacid ethyl ester

{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-[3-(1-methylcarbamoyl-2-phenyl-ethylcarbamoyl)-morpholin-4-yl]-methylene}-carbamicacid ethyl ester

N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(1H-indol-2-yl-amine)-propionamide

([1-(4-cyano-1-methyl-piperidin-4-yl-carbamoyl)-2-naphthalen-2-yl-ethylamino]-morpholin-4-yl-methylene)-carbamicacid ethyl ester

([1-(4-cyano-1-methyl-piperidin-4-yl-carbamoyl)-2-(6-dimethylaminomethy,naphthalen-2-yl-ethylamino]-morpholin-4-yl-methylene)-carbamicacid ethyl ester

2-(Benzooxazol-2-ylamino)-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide

2-(Benzooxazol-2-ylamino)-4,4-dimethyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

2-(Benzothiazol-2-ylamino)-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide

2-(Benzothiazol-2-ylamino)-4,4-dimethyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

2-(1H-Benzoimidazol-2-ylamino)-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide

2-(1H-Benzoimidazol-2-ylamino)-4,4-dimethyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(6-methanesulfonylamino-2H-indazol-3-ylamino)-propionamide

2-(6-Methanesulfonylamino-2H-indazol-3-ylamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide

2-(Benzo[d]isoxazol-3-ylamino)-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide

2-(Benzo[d]isoxazol-3-ylamino)-4,4-dimethyl-hexanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

2-(Benzo[d]isothiazol-3-ylamino)-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide

2-(Benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(7-methanesulfonylamino-imidazo[1,5-d]pyridin-3-ylamino)-propionamide

2-(7-Methanesulfonylamino-imidazo[1,5-a]pyridin-3-ylamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide

2-[1-(2-Carbamoyl-ethyl)-1H-imidazol-2-ylamino]-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide

N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(3-ureido-pyridin-2-ylamino)-propionamide

4,4-Dimethyl-2-(3-ureido-pyridin-2-ylamino)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

2-[1-(2-Carbamoyl-ethyl)-1H-imidazol-2-ylamino]-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide

4,4-Dimethyl-2-(4-trifluoromethyl-pyrimidin-2-ylamino)-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide

{[1-(1-Benzyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-methyl-carbamicacid ethyl ester

{[1-(4-Cyano-1-isopropyl-piperidin-4-ylcarbamoyl)-3-methyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid benzyl ester

{[1-(4-Cyano-1-ethyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid cyclopentyl ester

{[1-(4-Cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid 2-methoxy-ethyl ester

{[1-(4-Cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-phenyl-methylene}-carbamicacid ethyl ester

METHODS OF THERAPEUTIC USE

The compounds of the invention are useful in inhibiting the activity ofcathepsin S, K, F, L and B. In doing so, these compounds are useful inblocking disease processes mediated by these cysteine proteases.

Compounds of this invention effectively block degradation of theinvariant chain to CLIP by cathepsin S, and thus inhibit antigenpresentation and antigen-specific immune responses. Control of antigenspecific immune responses is an attractive means for treating autoimmunediseases and other undesirable T-cell mediated immune responses. Thus,there is provided methods of treatment using the compounds of thisinvention for such conditions. These encompass autoimmune diseases andother diseases involving inappropriate antigen specific immune responsesincluding, but not limited to, rheumatoid arthritis, systemic lupuserythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis,Guillain-Barre syndrome, psoriasis, Grave's disease, myasthenia gravis,scleroderma, glomerulonephritis, atopic dermatitis, insulin-dependentdiabetes mellitus and asthma. The compounds of the invention can also beused to treat other disorders associated with extracellular proteolysissuch as Alzheimer's disease and atherosclerosis. The compounds of theinvention can also be used to treat other disorders associated withinappropriate autoimmune responses, T-cell mediated immune responses, orextracellular proteolysis mediated by cathepsin S, unrelated to thoselisted above or discussed in the Background of the Invention. Therefore,the invention also provides methods of modulating an autoimmune diseasecomprising administering to a patient in need of such treatment apharmaceutically effect amount of a compound according to the invention.

Compounds of the invention also inhibit cathepsin K. In doing so, theymay block inappropriate degradation of bone collagen and other bonematrix proteases. Thus, there is provided a method for treating diseaseswhere these processes play a role such as osteoporosis. Inhibition ofcathepsins F, L, and B are also within the scope of the inventiondue tosimilarity of the active sites in cysteine proteases as described above.

For therapeutic use, the compounds of the invention may be administeredin any conventional dosage form in any conventional manner. Routes ofadministration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous.

The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutical compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. Advantageously, such combinationtherapies utilize lower dosages of the conventional therapeutics, thusavoiding possible toxicity and adverse side effects incurred when thoseagents are used as monotherapies. Compounds of the invention may bephysically combined with the conventional therapeutics or otheradjuvants into a single pharmaceutical composition. Advantageously, thecompounds may then be administered together in a single dosage form. Insome embodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 15%, but morepreferably at least about 20%, of a compound of the invention (w/w) or acombination thereof. Alternatively, the compounds may be administeredseparately (either serially or in parallel). Separate dosing allows forgreater flexibility in the dosing regime.

As mentioned above, dosage forms of the compounds of this inventioninclude pharmaceutically acceptable carriers and adjuvants known tothose of ordinary skill in the art. These carriers and adjuvantsinclude, for example, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 10-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. As theskilled artisan will appreciate, lower or higher doses may be requireddepending on particular factors. For instance, specific dosage andtreatment regimens will depend on factors such as the patient's generalhealth profile, the severity and course of the patient's disorder ordisposition thereto, and the judgment of the treating physician.

ASSESSMENT OF BIOLOGICAL PROPERTIES Expression and Purification ofRecombinant Human Cathepsin S

Cloning of human cathepsin S:

U937 RNA was subjected to reverse transcriptase/polymerase chainreaction with primer A (5′ cacaatgaaacggctggtttg 3′) and primer B (5′ctagatttctgggtaagaggg 3′) designed to specifically amplify the cathepsinS cDNA. The resulting 900 bp DNA fragment was subcloned into pGEM-T(Promega) and sequenced to confirm its identity. This construct was usedfor all subsequent manipulations. This procedure is typical for cloningof known genes and is established in its field.

Human Pre-Pro-Cat S was removed from pGem-T vector (Promega, 2800 WoodsHollow Rd, Madison, Wis. 53711) by digestion with restriction enzymeSalI, followed by treatment with T4 DNA polymerase to generate a bluntend, and a second restriction enzyme digest with SalI. It was subclonedinto pFastBacl donor plasmid (GibcoBRL, 8717 Grovemont Cr.,Gaithersburg, Md. 20884) which had been cut with restriction enzymeBanH1 and blunt-ended and then cut with restriction enzyme SalI. Theligation mixture was used to transform DH5a competent cells (GibcoBRL)and plated on LB plates containing 100 ug/ml ampicillin. Colonies weregrown in overnight cultures of LB media containing 50 ug/ml Ampicillin,plasmid DNA isolated and correct insert confirmed by restriction enzymedigestion. Recombinant pFastBac donor plasmid was transformed intoDH10Bac competent cells (GibcoBRL). Large white colonies were pickedfrom LB plates containing 50 ug/ml kanamycin, 7 ug/ml gentamicin, 10ug/ml tetracycline, 100 ug/ml Bluo-gal, and 40 μg/ml IPTG. DNA wasisolated and used to transfect Sf9 insect cells using CellFECTIN reagent(GibcoBRL). Cells and supernatant were harvested after 72 hours. Viralsupernatant was passaged twice and presence of Cat S confirmed by PCR ofthe supernatant.

SF9 cells were infected with recombinant baculovirus at a MOI of 5 for48-72 hrs. Cell pellet was lysed and incubated in buffer at pH 4.5 at 37for 2 hours to activate Cat S from pro-form to active mature form(Bromme, D & McGrath, M., Protein Science, 1996, 5:789-791. ) Presenceof Cat S was confirmed by SDS-PAGE and Western blot using rabbitanti-human proCat S.

Inhibition of Cathepsin S

Human recombinant cathepsin S expressed in Baculovirus is used at afinal concentration of 10 nM in buffer. Buffer is 50 mM Na Acetate, pH6.5, 2.5 mMEDTA, 2.5 mMTCEP. Enzyme is incubated with either compound orDMSO for 10 min at 37C. Substrate 7-amino-4-methylcoumarin,CBZ-L-valyl-L-valyl-L-arginineamide (custom synthesis by MolecularProbes) is diluted to 20 uM in water (final concentration of 5 uM),added to assay and incubated for additional 10 minutes at 37 C. Compoundactivity is measured by diminished fluorescence compared to DMSO controlwhen read at 360 nm excitation and 460 nm emission.

Examples listed above were evaluated for inhibition of cathepsin S inthe above assay. All had IC₅₀ values of 100 micromolar or below.

Inhibition of Cathepsin K, F, L and B

Inhibition of these enzymes by particular compounds of the invention maybe determined without undue experimentation by using art recognizedmethods as provided hereinbelow each of which is incorporated herein byreference:

Cathepsin B, and L assays are to be found in the following references:

1. Methods in Enzymology, Vol.244, Proteolytic Enzymes: Serine andCysteine Peptidases, Alan J. Barrett, ed.

Cathepsin K assay is to be found in the following reference:

2. Bromme, D., Okamoto, K., Wang, B. B., and Biroc, S. (1996) J. Biol.Chem. 271, 2126-2132.

Cathepsin F assays are to be found in the following references:

3. Wang, B., Shi, G. P., Yao, P. M., Li, Z., Chapman, H. A., and Bromme,D. (1998) J. Biol. Chem. 273, 32000-32008.

4. Santamaria, I., Velasco, G., Pendas, A. M., Paz, A., and Lopez-Otin,C (1999) J. Biol. Chem. 274, 13800-13809.

Preferred compounds to be evaluated for inhibition of Cathepsin K, F, Land B in the above assays desirably have IC₅₀ values of 100 micromolaror below.

What is claimed is:
 1. A compound of formula (I):

wherein: Het is piperidinyl, pyrrolidinyl or azetidinyl each beingsubstituted or unsubstituted with one or more R₅; Y is O; R₁ ispyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrazinyl orpiperazinyl; wherein R₁ is substituted or unsubstituted by one or moreR_(a); R_(a) is C1-5 alkyl, C3-7 cycloalkyl, phenyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-5 alkoxy, C1-5alkanoyl, C1-5alkanoyloxy, aryloxy, benzyloxy, C1-5alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-8 alkyl,aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, or R_(a) isC1-5 alkanoylamino, aroylamino, C1-5 alkylthio, arylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, C1-5 alkoxycarbonylamino,aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidinoor guanidino, R_(a) may be further substituted or unsubstituted by oneor more R_(b); R_(b) is C1-5 alkyl, C3-6 cycloalkyl, aryl, C1-5 alkoxy,aryloxy, benzyloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro,amidino or guanidino; R₂ is hydrogen or C1-3 alkyl; R₃ is hydrogen, C1-5alkyl, C2-5alkylene, C3-7 cycloalkyl, arylC1-3alkyl or aryl wherein R₃is substituted or unsubstituted by one or more R_(c); R_(c) is C1-5alkyl, C3-7 cycloalkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, C1-5 alkoxy, aryloxy, C1-5 alkanoyl, aroyl, C1-5alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(c) is C1-5 alkanoylamino, aroylamino, C1-5alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxideor sulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, halogen, hydroxy, oxo, carboxy, cyano, nitro, amidinoor guanidino, R_(c) may be further substituted or unsubstituted by oneor more R_(d); R_(d) is C1-5 alkyl, C3-6 cycloalkyl, aryl, arylalkyl,C1-5 alkoxy, aryloxy, arylC1-5alkoxy, aroyl, amino, halogen, hydroxy,oxo, carboxy, cyano, nitro, amidino or guanidino; R₄ is hydrogen or C1-3alkyl; R₅ is C1-5 alkyl chain optionally interrupted by one or two O orS, phenyl, naphthyl, arylC1-3alkyl, furanyl, thienyl, pyrrolyl,imidazolyl, pyridinyl, pyrimidinyl, C1-5 alkanoyl, aroyl, C1-5alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, carbamoyl whereinthe nitrogen atom may be independantly mono or disubstituted by C1-5alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyridinyl,benzimidazolyl or quinolinyl, or R₅ is C1-5 alkanoylamino, aroylamino,C1-5 alkylthio wherein the sulfur atom may be oxidised to a sulfoxide orsulfone, arylthio wherein the sulfur atom may be oxidised to a sulfoxideor sulfone, C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or disubstituted by alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyridinylcarbonyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl or arylsulfonyl,or R₅ is halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino orguanidino, R₅ may be further substituted or unsubstituted by one or moreR_(e); R_(e) is C1-5 alkyl, C3-6 cycloalkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,pyranyl, thiopyranyl, furanyl, thienyl pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl, benzoxazolyl, quinoxalinyl, C1-5 alkoxy, aryloxy, aroyl,amino wherein the nitrogen atom may be independently mono ordi-substituted by C1-5 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, furanyl, thienyl, pyrrolyl or pyridinyl, halogen, hydroxy,oxo, carboxy, cyano, nitro, benzyloxy, arylC1-3alkoxycarbonyl, amidinoor guanidino; X is O or S and the pharmaceutically acceptable acceptablesalts, esters, tautomers, individual isomers and mixtures of isomersthereof.
 2. The compound according to claim 1 wherein: Het ispiperidinyl or pyrrolidinyl each ring being substituted with one or moreR₅; R₁ is pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,pyrazinyl or piperazinyl; wherein R₁ is substituted or unsubstituted byone or more R_(a); R_(a) is C1-3 alkyl, phenyl, naphthyl, piperidinyl,indolinyl, morpholinyl, piperazinyl, furanyl, thienyl, benzimidazolyl,C1-3 alkoxy, C1-3 alkanoyl, phenoxy, naphthyloxy, benzyloxy, C1-3alkoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl, phenyl, piperidinyl,morpholinyl, piperazinyl, furanyl, thienyl or pyridinyl, or R_(a) isC1-5 alkanoylamino, benzoylamino, C1-3alkylsulfonyl, phenylsulfonyl,ureido wherein either nitrogen atom may be independently substituted byalkyl, phenyl, piperidinyl, morpholinyl, furanyl, thienyl or pyridinyl,C1-3 alkoxycarbonylamino, C1-5 alkylcarbamoyloxy, C1-5alkylsulfonylamino, phenylsulfonylamino, C1-5 alkylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl, phenyl, piperidinyl,morpholinyl, piperazinyl, fliranyl, thienyl or pyridinyl, halogen,hydroxy, oxo, carboxy, nitro or cyano, R_(a) may be further substitutedor unsubstituted by one or more R_(b); R_(b) is halogen, hydroxy,benzyloxy, oxo or cyano; R₂ is hydrogen; R₃ is C1-5 alkyl or C2-5alkylene, C4-6 cycloalkyl or benzyl wherein R₃ is substituted orunsubstituted by one or more R_(c); R_(c) is C1-4 alkyl, C5-3alkyltio,C1-3alkylsulfonyl, halogen, hydroxy, oxo, carboxy, nitro or cyano, R_(c)may be further substituted or unsubstituted by one or more R_(d); R_(d)is mthyl, phenyl, benzyl, benzyloxy, C1-3alkoxy, halogen, hydroxy, nitroor cyano; R₄ is hydrogen; R₅ is C1-4alkyl chain optionally interruptedby one O or S atom, phenyl, phenylC1-2alkyl, furanyl, pyrimidinyl,thienyl, C1-3 alkanoyl, benzoyl, C1-4 alkoxycarbonyl, carbamoyl whereinthe nitrogen atom may be independently mono or disubstituted by C1-5alkyl, phenyl, piperidinyl, morpholinyl, piperazinyl, furanyl, thienylor pyridinyl, C1-3 alkylthio, phenyltio, C1-5 alkylaminosulfonyl,phenylaminosulfonyl, C1-5alkylamino wherein the nitrogen atom may beindependently mono- or disubstituted by naphthylsulfonyl orpyridinylcarbonyl, halogen, hydroxy, carboxy, oxo or cyano, R₅ may befurther substituted or unsubstituted by one or more R_(e); R_(e) is C1-3alkyl, C5-6 cycloalkyl, phenyl, naphthylmethyl, piperidinyl,morpholinyl, piperazinyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl,benzimidazolyl, quinolinyl, isoquinolinyl, C1-4 alkoxy, benzoyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, phenyl, piperidinyl, morpholinyl, furanyl, thienyl orpyridinyl, halogen, hydroxy, oxo or cyano; and X is O.
 3. The compoundaccording to claim 2 wherein: R₁ is piperidinyl, morpholinyl,piperazinyl or pyrazinyl; wherein R₁ is substituted or unsubstituted byone or more R_(a); R_(a) is C1-3 alkyl, phenyl, piperidinyl, thienyl,C1-3 alkoxy, phenoxy, C1-3alkanoyl, C1-3 alkoxycarbonyl, benzyloxy, C1-3alkanoylamino, thiophenyl, benzimidazolyl, C1-3 alkylthio or chloro,R_(a) may be further substituted or unsubstituted by one or more R_(b);R_(b) is bromo, chloro, fluoro, iodo, hydroxy, oxo or cyano; R₃ ismethyl, ethyl, n-propyl, n-butyl, isobutyl, propenyl, butenyl,isobutenyl, C3-7 cycloalkyl or benzyl wherein R₃ is substituted orunsubstituted by one or more R_(c); R_(c) is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, methylthio,ethylthio, cyclohexyl, phenyl, naphthyl, imidazolyl, indolinyl, bromo,chloro, fluoro, iodo, hydroxy, oxo, carboxy, nitro, benzoyl, benzyloxy,N-benzylimidazolyl or cyano, R_(c) may be further substituted orunsubstituted by one or more R_(d); R_(d) is methyl, methoxy, ethoxy,chloro, fluoro, nitro or hydroxy; R₅ is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutyloxycarbonyl, tert-butoxycarbonyl and pyrimidinyl, R₅ may befurther substituted or unsubstituted by one or more R_(c); and R_(e) ismethyl, ethyl, n-propyl, isopropyl, phenyl, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, tert-butoxycarbonyl, bromo, chloro,fluoro, iodo, hydroxy, oxo or cyano.
 4. The compound according to claim3 wherein: R₁ is morpholinyl or pyrazinyl; R₃ is n-butyl, isobutyl,2,2-dimethylpropyl, cyclohexylmethyl, p-methoxybenzyl or2-naphthylmethyl; and wherein the configuration at the asymmetric carbonatom defined by R₂ and R₃ when they are different is the L enantiomer;and R₅ is methyl, propyl, isopropyl, ethoxycarbonyl, benzyloxycarbonyl,benzyl, phenethyl, N,N-dimethylaminoacetyl or pyrimidinyl.
 5. Thecompound according to claim 4 wherein: Het is piperidin-4-yl orpyrrolidinyl; R₁ is morpholinyl; R₃ is 2,2-dimethylpropyl orcyclohexylmethyl; and R₅ is methyl, propyl, isopropyl, ethoxycarbonyl,benzyloxycarbonyl, benzyl, phenethyl, N,N-dimethylaminoacetyl orpyrimidinyl.
 6. A compound of formula (II):

wherein: Het is piperidinyl, pyrrolidinyl or azetidinyl each beingsubstituted or unsubstituted with one or more R₅; Y is C(O); R₁ is apyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrazinyl orpiperazinyl; wherein R₁ is substituted or unsubstituted by one or moreR_(a); R_(a) is a bond, C1-10 alkyl, C3-8 cycloalkyl, aryl,tetrahydronaphthyl, indenyl, indanyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, C1-10 alkoxy, C1-10alkanoyl,C1-10alkanoyloxy, aryloxy, benzyloxy, C1-10 alkoxycarbonyl,aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,fuiranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzoftiranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl, or R_(a) is C1-10 alkanoylamino,aroylamino, C1-10 alkylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidizedto a sulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by C1-10 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl, or R_(a) is C1-10 alkoxycarbonylamino,aryloxycarbonylamino, C1-10 alkylcarbamoyloxy, arylcarbamoyloxy, C1-10alkylsulfonylamino, arylsulfonylamino, C1-10 alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(a) is halogen, hydroxy, oxo, carboxy, cyano,nitro, carboxamide, amidino or guanidino, R_(a) may be furthersubstituted or unsubstituted by one or more R_(b); with the proviso thatR_(1 and R) _(a) simultaneously cannot be a bond; R_(b) is a C1-6saturated or unsaturated branched or unbranched carbon chain optionallypartially or fully halogenated wherein one or more carbon atoms areoptionally replaced by O, N, S(O), S(O)₂ or S and wherein said chain isoptionally independently substituted with 1-2 oxo groups, —NH₂, or oneor more C1-4 alkyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl; or R_(b) is C3-6 cycloalkyl, aryl, aryloxy, benzyloxy,halogen, hydroxy, oxo, carboxy, cyano, nitro, mono-C1-5alkylamino,di-C1-5alkylamino, carboxamide, amidino or guanidino; R₂ is hydrogen orC1-3 alkyl; R₃ is a bond, hydrogen, C1-10 alkyl, C2-10alkylene, C3-8cycloalkyl, arylC1-5alkyl or aryl wherein R₃ is substituted orunsubstituted by one or more R_(c); R_(c) is C1-10 alkyl, C3-8cycloalkyl, aryl, indanyl, indenyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl,bicyclo[1.1.1]pentanyl, cubanyl, 1,2,3,4-tetrahydronaphthyl,decahydronaphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, tetrahydrofuranyl,pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, dihydrobenzofuranyl,octohydrobenzofuranyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, tetrahydroquinolinyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-10 alkoxy, aryloxy, C1-10 alkanoyl, aroyl, C1-10 alkoxycarbonyl,aryloxycarbonyl, C1-10 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, or R_(c) isC1-10 alkanoylamino, aroylamino, C1-10 alkylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-10 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzoftiranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R_(c) is C1-10alkoxycarbonylamino, aryloxycarbonylamino, C1-10 alkylcarbamoyloxy,arylcarbamoyloxy, C1-10 alkylsulfonylamino, arylsulfonylamino, C1-10alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-10 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R_(c) is halogen,hydroxy, oxo, carboxy, cyano, nitro, amidino or guanidino, R_(c) may befurther substituted or unsubstituted by one or more R_(d); R_(d) is C1-5alkyl, C3-6 cycloalkyl, aryl, arylC1-5alkyl, C1-5 alkoxy, aryloxy,arylC1-5alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino or guanidino; R₂ and R₃ together with the carbon they areattached optionally form a nonaromatic 5-7 membered cycloalkyl orheterocyclic ring; R₄ is hydrogen, hydroxy or C1-3 alkyl; R₅ is a bond,hydrogen, carbonyl, C1-10 alkyl, C1-10alkoxyC1-10alkyl,C1-10alkylaminoC1-10alkyl, C1-10alkylthioC1-10alkyl wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, C1-10 alkoxy, aryloxy,C3-8 cycloalkyl, aryl, benzyl, tetrahydronaphthyl, indenyl, indanyl,C3-7cycloalkylsulfonylC1-5alkyl, arylsulfonylc 1-5alkyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, thiopyranyl,tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridizinyl, tetrazolyl, triazolyl, pyrazolyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,quinazolinyl, tetrahydroquinazolinyl, benzoxazolyl and quinoxalinyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from theheterocyclyl moieties herein described in this paragraph, C1-10alkanoyl,aroyl, C1-10alkanoyloxy, benzyloxy, C1-10alkoxycarbonyl,arylC1-5alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, or R₅ is C1-10alkanoylamino, aroylamino, C1-10 alkylthio wherein the sulfur atom maybe oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-10 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R₅ is C1-10alkoxycarbonylamino, aryloxycarbonylamino, C1-10 alkylcarbamoyloxy,arylcarbamoyloxy, C1-10 alkylsulfonylamino, arylsulfonylamino, C1-10alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-10 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R₅ is halogen, hydroxy,oxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino, R₅may be further substituted or unsubstituted by one or more R_(e); R_(e)is C1-10 alkyl, C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl,C1-10alkylthioC1-10alkyl wherein the sulfur atom may be oxidized to asulfoxide or sulfone, C1-10 alkoxy, C3-8 cycloalkyl, aryl,tetrahydronaphthyl, indenyl, indanyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, thiopyranyl,tetrahydrothiopyranyl, pyranyl, tetrahydropyranyl, tetrahydrofuranyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-10alkanoyl, aroyl, C1-10 alkanoyloxy, aryloxy, benzyloxy, C1-10alkoxycarbonyl, arylC1-3alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(e) is C1-10 alkanoylamino, aroylamino, C1-10alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxideor sulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(e) is C1-10 alkoxycarbonylamino,aryloxycarbonylamino, C1-10 alkylcarbamoyloxy, arylcarbamoyloxy, C1-10alkylsulfonylamino, arylsulfonylamino, C1-10 alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(e) is halogen, hydroxy, oxo, carboxy, cyano,nitro, carboxamide, amidino or guanidino, R_(e) may be furthersubstituted or unsubstituted by one or more R_(f); R_(f) is C1-5 alkyl,C3-6 cycloalkyl, tolylsulfonyl, C1-5 alkoxy, aryl, aryloxy, benzyloxy,halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino orguanidino; X is O and the pharmaceutically acceptable acceptable salts,esters, tautomers, individual isomers and mixtures of isomers thereof.7. The compound according to claim 6 wherein: R₁ is pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or pyrazinyl;wherein R₁ is substituted or unsubstituted by one or more R_(a); R_(a)is a bond C1-7 alkyl, C3-6 cycloalkyl, phenyl, naphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, C1-7 alkoxy, C1-7alkanoyl, C1-7 alkanoyloxy,aryloxy, benzyloxy, C1-7 alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-7 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,or R_(a) is C1-7 alkanoylamino, aroylamino, C1-7 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-7alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R_(a) is C1-7alkoxycarbonylamino, aryloxycarbonylamino, C1-7 alkylcarbamoyloxy,arylcarbamoyloxy, C1-7 alkylsulfonylamino, arylsulfonylamino, C1-7alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-7 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl, or R_(a) is halogen, hydroxy, oxo,carboxy, cyano, nitro, carboxamide, amidino or guanidino, R_(a) may befurther substituted or unsubstituted by one or more R_(b); R_(b) is C1-5alkyl, C3-6 cycloalkyl, aryl, C1-5 alkoxy, aryloxy, benzyloxy, halogen,hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino;R₂ is hydrogen or methyl or ethyl; R₃ is a bond, hydrogen, C1-5 alkyl,C2-5alkylene, C3-7 cycloalkyl, arylC1-3alkyl or aryl wherein R₃ issubstituted or unsubstituted by one or more R_(c); R_(c) is C1-5 alkyl,C3-7 cycloalkyl, aryl, indanyl, indenyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl,bicyclo[1.1.1]pentanyl, cubanyl, 1,2,3,4-tetrahydronaphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, C1-5 alkoxy, aryloxy, C1-5alkanoyl, aroyl, C1-5 alkoxycarbonyl, aryloxycarbonyl, C1-5 alkanoyloxy,aroyloxy, carbamoyl wherein the nitrogen atom may be independently monoor di-substituted by C1-5 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(a) is C1-5 alkanoylamino, aroylamino, C1-5alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxideor sulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(c) is C1-5 alkoxycarbonylamino,aryloxycarbonylamino, C1-5 alkylcarbamoyloxy, arylcarbamoyloxy, C1-5alkylsulfonylamino, arylsulfonylamino, C1-5 alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-5 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(c) is halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino or guanidino, R_(c) may be further substituted orunsubstituted by one or more R_(d); R_(d) is C1-5 alkyl, C3-6cycloalkyl, aryl, arylC1-4 alkyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy,aroyl, halogen, hydroxy, oxo or cyano; R₄ is hydrogen or methyl; R₅ is abond, hydrogen, carbonyl, C1-8 alkyl, C1-8alkoxyC1-8alkyl,C1-8alkylaminoC1-8alkyl, C1-8alkylthioC1-8alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-8 alkoxy, aryloxy, C3-7cycloalkyl, aryl, benzyl, tetrahydronaphthyl, indanyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, thiopyranyl,tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, tetrazolyl,triazolyl, pyrazolyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,benzoxazolyl and quinoxalinyl, heterocyclyloxy wherein the heterocyclylmoiety is selected from the heterocyclyl moieties herein described inthis paragraph, C1-7alkanoyl, aroyl, C1-7alkanoyloxy, benzyloxy, C1-7alkoxycarbonyl, arylC1-4alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-7 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R₅ is C1-7alkanoylamino, aroylamino, C1-7 alkylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom maybe oxidized to a sulfoxide or sulfone, ureido wherein either nitrogenatom may be independently substituted by C1-7 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,or R₅ is C1-7 alkoxycarbonylamino, aryloxycarbonylamino, C1-7alkylcarbamoyloxy, arylcarbamoyloxy, C1-7 alkylsulfonylamino,arylsulfonylamino, C1-7 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-7 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R₅ is halogen, hydroxy,oxy, oxo, carboxy, cyano, nitro or carboxamide, R₅ may be furthersubstituted or unsubstituted by one or more R_(e); R_(e) is C1-7 alkyl,C1-7alkoxyC1-7alkyl, C1-7alkylaminoC1-7alkyl, C1-7alkylthioC1-7alkylwherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-7alkoxy, C3-7 cycloalkyl, aryl, tetrahydronaphthyl, indanyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,thiopyranyl, tetrahydrothiopyranyl, tetrahydropyranyl,tetrahydrofuranyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, C1-5 alkanoyl, aroyl, C1-5alkanoyloxy,aryloxy, benzyloxy, C1-5 alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-5 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R_(e) is C1-5alkanoylamino, aroylamino, C1-5 alkylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atom maybe oxidized to a sulfoxide or sulfone, ureido wherein either nitrogenatom may be independently substituted by C1-5 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,or R_(e) is C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl, or R_(e) is halogen, hydroxy, oxo,carboxy, cyano, nitro, carboxamide, amidino or guanidino, R_(e) may befurther substituted or unsubstituted by one or more R_(f); and R_(f) ismethyl, ethyl, t-butyl, tolylsulfonyl, C1-3 alkoxy, cyclopropyl,cyclohexyl, phenyl, naphthyl, phenoxy, benzyloxy, fluoro, chloro, bromo,hydroxy, oxo, carboxy, cyano, nitro or carboxamide.
 8. The compoundaccording to claim 7 wherein: R_(a) is a bond, C1-3 alkyl, cyclopropyl,cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl,benzthiazolyl, benzoxazolyl, C1-3 alkoxy, C1-3alkanoyl, C1-3alkanoyloxy,aryloxy, benzyloxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-3 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl, orR_(a) is C1-3 alkanoylamino, aroylamino, C1-3 alkylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, arylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, ureidowherein either nitrogen atom may be independently substituted by C1-3alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl orpiperazinyl, or R_(a) is C1-3 alkoxycarbonylamino, aryloxycarbonylamino,C1-3 alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino,arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl, or R_(a) is halogen, hydroxy, oxo,carboxy, cyano, nitro, carboxamide, amidino or guanidino, R_(a) may befurther substituted or unsubstituted by one or more R_(b); R_(b) is C1-3alkyl, C3-6 cycloalkyl, aryl, C1-3 alkoxy, aryloxy, benzyloxy, halogen,hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino;R₂ is hydrogen or methyl; R₃ is a bond, hydrogen, C1-5 alkyl,C2-5alkylene, C4-6 cycloalkyl or arylC1-2alkyl wherein R₃ is substitutedor unsubstituted by one or more R_(c); R_(c) is C1-4 alkyl, C5-6cycloalkyl, phenyl, naphthyl, indanyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl,bicyclo[1.1.1]pentanyl, cubanyl, 1,2,3,4-tetrahydronaphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, indolinyl,furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, C1-4 alkoxy, phenoxy, naphthyloxy, C1-3 alkanoyl, benzoyl,C1-3 alkoxycarbonyl, phenoxycarbonyl, C1-3 alkanoyloxy, benzoyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-5 alkyl or aryl, or R_(c) is C1-3 alkanoylamino,benzoylamino, C1-3 alkylthio wherein the sulfur atom may be oxidized toa sulfoxide or sulfone, phenylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atommay be independently substituted by C1-5 alkyl or aryl, or R_(c) is C1-3alkoxycarbonylamino, aryloxycarbonylamino, C1-3 alkylcarbamoyloxy,arylcarbamoyloxy, C1-3 alkylsulfonylamino, arylsulfonylamino, C1-3alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-5 alkyl or aryl, orR_(c) is halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino orguanidino, R_(c) may be further substituted or unsubstituted by one ormore R_(d); R_(d) is C1-3 alkyl, C3-6 cycloalkyl, phenyl, benzyl, C1-3alkoxy, phenoxy, phenylC1-3alkoxy, benzoyl, halogen, hydroxy, oxo orcyano; R₄ is hydrogen; R₅ is a bond, hydrogen, carbonyl, C1-6 alkyl,C1-6alkoxyC1-6alkyl, C1-6alkylaminoC1-6alkyl, C1-6alkylthioC1-6alkylwherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-6alkoxy, phenoxy, naphthyloxy, C3-6 cycloalkyl, phenyl, naphthyl, benzyl,indanyl, heterocyclyl selected from pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl,tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyland benzoxazolyl, heterocyclyloxy wherein the heterocyclyl moiety isselected from the heterocyclyl moieties herein described in thisparagraph, C1-3alkanoyl, benzoyl, naphthoyl, C1-4alkanoyloxy, benzyloxy,C1-4 alkoxycarbonyl, arylC1-2alkoxycarbonyl, phenoxycarbonyl,benzoyloxy, carbamoyl wherein the nitrogen atom may be independentlymono or di-substituted by C1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl orpyrimidinyl, or R₅ is C1-4 alkanoylamino, aroylamino, C1-4 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl or benzthiazolyl, or R₅ is C1-4 alkoxycarbonylamino,phenoxycarbonylamino, C1-4 alkylcarbamoyloxy, phenylcarbamoyloxy, C1-4alkylsulfonylamino, phenylsulfonylamino, C1-3 alkylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by C1-4 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,benzimidazolyl or benzthiazolyl, or R₅ is halogen, hydroxy, oxo,carboxy, cyano, nitro or carboxamide, R₅ may be further substituted orunsubstituted by one or more R_(e); R_(e) is C1-4 alkyl, C1-4 alkoxy,C3-7 cycloalkyl, phenyl, naphthyl, indanyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrothiopyranyl,tetrahydropyranyl, tetrahydrofuranyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl,benzthiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, C1-4 alkanoyl, aroyl, C1-4alkanoyloxy, phenoxy,naphthyloxy, benzyloxy, C1-4 alkoxycarbonyl, phenoxycarbonyl,benzoyloxy, carbamoyl wherein the nitrogen atom may be independentlymono or di-substituted by C1-3 alkyl, phenyl, naphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,benzimidazolyl, or benzthiazolyl, or R_(e) is C1-4 alkanoylamino,benzoylamino, C1-4 alkylthio wherein the sulfur atom may be oxidized toa sulfoxide or sulfone, phenylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atommay be independently substituted by C1-3 alkyl, phenyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, benzimidazolyl or benzthiazolyl, or R_(e) is C1-4alkoxycarbonylamino, phenoxycarbonylamino, C1-4 alkylcarbamoyloxy,phenylcarbamoyloxy, C1-4 alkylsulfonylamino, phenylsulfonylamino, C1-4alkylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-3 alkyl, phenyl,naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl, or R_(e) ishalogen, hydroxy, oxo, carboxy, cyano, nitro or carboxamide, R_(e) maybe further substituted or unsubstituted by one or more R_(f); and R_(f)is methyl, ethyl, t-butyl, tolylsulfonyl, methoxy, cyclopropyl, phenyl,phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy, oxo, carboxy orcarboxamide.
 9. The compound according to claim 8 wherein: R_(a) is abond, C1-3 alkyl, cyclopropyl, cyclohexyl, phenyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, thienyl,imidazolyl, C1-3 alkoxy, C1-3alkanoyl, C1-3alkanoyloxy, aryloxy,benzyloxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl, or R_(a) is C1-3 alkanoylamino,aroylamino, C1-3 alkylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidizedto a sulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by C1-3 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, or R₁ is C1-3alkoxycarbonylamino, aryloxycarbonylamino, C1-3 alkylcarbamoyloxy,arylcarbamoyloxy, C1-3 alkylsulfonylamino, arylsulfonylamino, C1-3alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-3 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further substituted or unsubstitutedby one or more R_(b); R_(b) is methyl, ethyl, n-propyl, i-propyl,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy,n-propoxy, i-propoxy, phenoxy, benzyloxy, fluoro, chloro, bromo, iodo,hydroxy, oxo, carboxy, cyano, nitro or carboxamide; R₂ is hydrogen; R₃is a bond, C1-3 alkyl, C2-4alkylene, C5-6 cycloalkyl, benzyl ornaphthylmethyl wherein R₃ is substituted or unsubstituted by one or moreR_(c); R_(c) is C1-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, indanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, fulranyl, tetrahydropyranyl, thienyl,oxazolyl, thiazolyl, imidazolyl, pyrimidinyl, indolyl, benzofuranyl,benzothienyl, benzthiazolyl, C1-3 alkoxy, phenoxy, naphthyloxy, C1-2alkanoyl, benzoyl, C1-2 alkoxycarbonyl, phenoxycarbonyl,C1-2alkanoyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or aryl, or R_(c) isC1-2 alkanoylamino, benzoylamino, C1-2 alkylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-3 alkyl or aryl, orR_(c) is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, arylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl or phenyl, or R_(c) is halogen, hydroxy, oxo, carboxy orcyano, R_(c) may be further substituted or unsubstituted by one or moreR_(d); R_(d) is methyl, cyclopropyl, cyclohexyl, phenyl, benzyl,methoxy, phenoxy, benzyloxy, benzoyl, fluoro, chloro, oxo or cyano; R₅is a bond, hydrogen, carbonyl, C1-5 alkyl, C1-5alkoxyC1-5alkyl,C1-5alkylaminoC1-5alkyl, C1-5alkylthioC1-5alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-5 alkoxy, phenoxy, C3-6cycloalkyl, phenyl, naphthyl, benzyl, indanyl, heterocyclyl selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl and benzthiazolyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from theheterocycyl moieties herein described in this paragraph, C1-3alkanoyl,benzoyl, naphthoyl, C1-3alkanoyloxy, benzyloxy, C1-3 alkoxycarbonyl,benzyloxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl, or R₅ is C1-3alkanoylamino, aroylamino, C1-3 alkylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, phenylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-3 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzofuranyl,benzothienyl, benzimidazolyl or benzthiazolyl, or R₅ is C1-3alkoxycarbonylamino, phenoxycarbonylamino, C1-3 alkylcarbamoyloxy,phenylcarbamoyloxy, C1-3 alkylsulfonylamino, phenylsulfonylamino, C1-3alkylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-3 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolylor benzthiazolyl, or R₅ is halogen, hydroxy, oxo, carboxy, cyano orcarboxamide, R₅ may be further substituted or unsubstituted by one ormore R_(e); R_(e) is C1-3 alkyl, C1-3 alkoxy, C3-7 cycloalkyl, phenyl,naphthyl, indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,C1-3 alkanoyl, aroyl, C1-3alkanoyloxy, phenoxy, benzyloxy, C1-3alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl orbenzthiazolyl, or R_(e) is C1-3 alkanoylamino, benzoylamino, C1-3alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, phenylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by C1-3 alkyl, phenyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl, or R_(e) isC1-3 alkoxycarbonylamino, phenoxycarbonylamino, C1-3 alkylcarbamoyloxy,phenylcarbamoyloxy, C1-3 alkylsulfonylamino, phenylsulfonylamino, C1-3alkylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-3 alkyl, phenyl,naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl orbenzthiazolyl, or R_(e) is halogen, hydroxy, oxo, carboxy, cyano orcarboxamide, R_(e) may be further substituted or unsubstituted by one ormore R_(f); and R_(f) is methyl, phenyl, tolylsulfonyl, methoxy,phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy, oxo, carboxy orcarboxamide.
 10. The compound according to claim 9 wherein: R_(a) is abond, methyl, ethyl, cyclopropyl, phenyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, thienyl, imidazolyl, methoxy,acetyl, acetoxy, phenoxy, benzyloxy, methoxycarbonyl, phenoxycarbonyl,benzoyloxy, carbamoyl wherein the nitrogen atom may be independentlymono or di-substituted by methyl, ethyl or phenyl, or R_(a) isacetylamino, benzoylamino, methylthio, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl orphenyl, or R_(a) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl, or R_(a) is fluoro, chloro, bromo, iodo, hydroxy, oxo,carboxy, cyano, nitro or carboxamide, R_(a) may be further substitutedor unsubstituted by one or more R_(b); R_(b) is methyl, cyclopropyl,phenyl, methoxy, phenoxy, benzyloxy, fluoro, chloro, hydroxy, oxo,carboxy or carboxamide; R₃ is a bond, C1-3 alkyl, C2-4alkylene, C5-6cycloalkyl, benzyl or naphthylmethyl wherein R₃ is substituted orunsubstituted by one or more R_(c); R_(c) is methyl, ethyl, n-propyl,i-propyl, C5-6 cycloalkyl, indanyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl,bicyclo[1.1.1]pentanyl, cubanyl, 1,2,3,4-tetrahydronaphthyl, thienyl,oxazolyl, thiazolyl, indolyl, benzofuranyl, benzothienyl, benzthiazolyl,methoxy, ethoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl,phenoxycarbonyl, acetoxy, benzoyloxy, carbamoyl wherein the nitrogenatom may be independently mono or di-substituted by methyl, ethyl oraryl, or R_(c) is acetylamino, benzoylamino, methylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl or aryl, or R_(c) is methoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl, orR_(c) is fluoro, chloro or oxo, R_(c) may be further substituted orunsubstituted by one or more R_(d); R_(d) is methyl, cyclopropyl,phenyl, methoxy, fluoro, chloro or oxo; R₅ is a bond, hydrogen,carbonyl, C1-4 alkyl, C1-4alkoxyC1-4alkyl, C1-4alkylaminoC1-4alkyl,C1-4alkylthioC1-4alkyl wherein the sulfur atom may be oxidized to asulfoxide or sulfone, C1-4 alkoxy,phenoxy, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, naphthyl, benzyl, indanyl, heterocyclyl selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, benzimidazolyl and benzthiazolyl, heterocyclyloxy whereinthe heterocyclyl moiety is selected from the heterocycyl moieties hereindescribed in this paragraph, C1-2alkanoyl, benzoyl, naphthoyl,C1-2alkanoyloxy, benzyloxy, C1-2 alkoxycarbonyl, benzyloxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl, or R₅ is C1-2alkanoylamino, benzoylamino, C1-2 alkylthio wherein the sulfur atom maybe oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl orbenzthiazolyl, or R₅ is C1-2 alkoxycarbonylamino, phenoxycarbonylamino,C1-2 alkylcarbamoyloxy, phenylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl, or R₅ isfluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide, R₅ may befurther substituted or unsubstituted by one or more R_(e); R_(e) is C1-3alkyl, C1-2 alkoxy, C3-6 cycloalkyl, phenyl, naphthyl, indanyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl,indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, C1-2 alkanoyl,aroyl, C1-2alkanoyloxy, phenoxy, benzyloxy, C1-2 alkoxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl, or R_(e) is C1-2alkanoylamino, benzoylamino, C1-2 alkylthio wherein the sulfur atom maybe oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl, or R_(e) is C1-2alkoxycarbonylamino, phenoxycarbonylamino, C1-2 alkylcarbamoyloxy,phenylcarbamoyloxy, C1-2 alkylsulfonylamino, phenylsulfonylamino, C1-2alkylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-2 alkyl, phenyl,naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl, or R_(e) is fluoro,chloro, bromo, hydroxy, oxo, carboxy or carboxamide, R_(e) may befurther substituted or unsubstituted by one or more R_(f); and R_(f) ismethyl, phenyl, tolylsulfonyl, methoxy, phenoxy, benzyloxy, fluoro,chloro, hydroxy, oxo, carboxy or carboxamide.
 11. The compound accordingto claim 10 wherein: Het is piperidin-4-yl, piperidin-3-yl,pyrrolidin-3-yl, azetidin-3-yl, each ring being substituted orunsubstituted with one or more R₅; R_(a) is methyl, phenyl, thienyl,methoxy, acetyl, acetoxy, phenoxy, benzyloxy, methoxycarbonyl,benzoyloxy, carbamoyl wherein the nitrogen atom may be independentlymono or di-substituted by methyl or phenyl, or R_(a) is acetylamino,methylthio, phenylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by methyl or phenyl, or R_(a) ismethoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, amino wherein the nitrogenatom may be independently mono or di-substituted by methyl or phenyl, orR_(a) is fluoro, chloro, hydroxy, oxo, carboxy, cyano or carboxamide; R₃is a bond, methyl, ethyl, n-propyl, propenyl, butenyl, i-butenyl,cyclohexyl, benzyl or naphthylmethyl wherein R₃ is substituted orunsubstituted by one or more R_(c); R_(c) is methyl, ethyl, n-propyl,i-propyl, cyclohexyl, cyclopentyl, indanyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl, bicyclo [3.1.1]hexanyl,bicyclo [1.1.1]pentanyl, cubanyl, 1,2,3,4-tetrahydronaphthyl, methoxy,phenoxy, acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, acetoxy,benzoyloxy, methylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, phenylthio wherein the sulfur atom may be oxidizedto a sulfoxide or sulfone, fluoro, chloro or oxo; R₅ is a bond,hydrogen, carbonyl, C1-4 alkyl, C1-2alkoxyC1-2alkyl,C1-2alkylaminoC1-2alkyl, C1-2alkylthioC1-2alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-2 alkoxy, phenoxy,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl,pyridinyl, and pyrimidinyl, heterocyclyloxy wherein the heterocyclylmoiety is selected from the heterocycyl moieties herein described inthis paragraph, acetyl, benzoyl, acetyloxy, benzyloxy, methoxycarbonyl,ethoxycarbonyl, benzyloxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl, or R₅ is acetylamino, benzoylamino, methylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl or phenyl, or R₅ is methoxycarbonylamino,ethoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy,phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino,methylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogenatom may be independently mono or di-substituted by methyl, ethyl orphenyl, or R₅ is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide,R₅ may be further substituted or unsubstituted by one or more R_(c);R_(c) is methyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl,phenyl, naphthyl, indanyl, piperidinyl, morpholinyl, indolyl, thienyl,pyridinyl, acetyl, benzoyl, acetyloxy, phenoxy, benzyloxy,methoxycarbonyl, ethoxycarbonyl, carbamoyl wherein the nitrogen atom maybe independently mono or di-substituted by methyl, ethyl or phenyl, orR_(e) is acetylamino, benzoylamino, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl orphenyl, or R_(e) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl, orR_(c) is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R_(c) maybe further substituted or unsubstituted by one or more R_(f); and R_(f)is methyl, phenyl, tolylsulfonyl, phenoxy, benzyloxy, fluoro, chloro oroxo.
 12. The compound according to claim 11 wherein: R₃ is ethyl,n-propyl,propenyl, butenyl, i-butenyl, benzyl or naphthylmethyl whereinR₃ is substituted or unsubstituted by one or more R_(c); R_(c) ismethyl, cyclohexyl, cyclopentyl, indanyl, 1,2,3,4-tetrahydronaphthyl,methoxy, methylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, fluoro or chloro; R₅ is a bond, carbonyl, methyl,ethyl, n-propyl, n-butyl, t-butyl, i-propyl, i-butyl, cyclopropyl,cyclopentyl, cyclohexyl, phenyl, benzyl, piperidinyl, tetrahydropyranyl,pyrimidinyl, acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl,methylsulfonylamino, phenylsulfonylamino, methylamino, dimethylamino,fluoro, oxo or carboxy, R₅ may be further substituted or unsubstitutedby one or more R_(e); and R_(e) is methyl, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, naphthyl, indanyl, thienyl, 5-methylthienyl,methoxy, phenoxy, benzyloxy, piperidinyl, pyridinyl, indolyl,1-(tolyl-sulfonyl)-indolyl, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by methyl, phenyl or benzyl, orR_(c) is hydroxy, fluoro, chloro, oxo, dimethylamino or trifluoromethyl.13. The compound according to claim 12 wherein: R₁ is morpholinyl,pyrrolidinyl, piperidinyl, piperazinyl or pyrazinyl; R₃ is n-butyl,i-butyl, 2,2-dimethylpropyl, cyclohexylmethyl, propenyl, i-butenyl,4-methoxybenzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 3-chlorobenzyl,2,4-dichlorobenzyl, 4-methylbenzyl, 3-methylbenzyl or naphth-2-ylmethyl;wherein the configuration at the asymmetric carbon atom defined by R₂and R₃ when they are different is the L enantiomer; and R₅ is a bond,methyl, ethyl, n-propyl, n-butyl, n-pentyl, 2-pentyl, 3-pentyl,phenethyl, phenpropyl, 2,2-dimethylpropyl, t-butyl, i-propyl, i-butyl,cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, naphthylmethyl,indanylmethyl, pyridinylmethyl, indolylmethyl, thienylmethyl,5-methylthienylmethyl, piperidinyl, piperidinylcarbonyl,pyridinylcarbonyl, tetrahydropyranyl, pyrimidinyl, acetyl, benzoyl,ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, methylcarbamoyl,phenylcarbamoyl, benzylcarbamoyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, methylcyclohexyl,methylbenzyl, methoxybenzyl, phenoxybenzyl, benzyloxybenzyl,N-[(4-methylphenyl)-sulfonyl]-indolylmethyl, fluorobenzyl,difluorobenzyl, chlorobenzyl, N,N-dimethylaminoacetyl,trifluoromethylbenzyl, fluoro, oxo or carboxy.
 14. The compoundaccording to claim 8 wherein: R_(a) is methyl, ethyl, propyl, i-propyl,cyclopropyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, thienyl, imidazolyl, methoxy, ethoxy,acetyl, acetoxy, phenoxy, naphthyloxy, benzyloxy, methoxycarbonyl,ethoxycarbonyl, phenoxycarbonyl, naphthyloxycarbonyl, benzoyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by methyl, ethyl, phenyl, naphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, or R_(a) isacetylamino, benzoylamino, methylthio wherein the sulfur atom may beoxidized to a sulfoxide of sulfone, ehtylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl, phenyl,naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl orpiperazinyl, or R_(a) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, C1-2 alkylcarbamoyloxy, phenylcarbamoyloxy,naphthylcarbamoyyloxy, C1-2 alkysulfonylamino, phenylsulfonylamino,naphthylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl,naphthylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl, phenyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further substituted or unsubstitutedby one or more R_(b); R_(b) is methyl, ethyl, cyclopropyl, cyclohexyl,phenyl, methoxy, ethoxy, phenoxy, benzyloxy, fluoro, chloro, bromo,hydroxy, oxo, carboxy, cyano, nitro or carboxamide; R₂ is hydrogen ormethyl; R₃ is a bond, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, n-pentyl, propenyl, i-butenyl, cyclohexyl, benzyl ornaphthylmethyl wherein R₃ is substituted or unsubstituted by one or moreR_(c); R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl,naphthyl, bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,furanyl, tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyrimidinyl, methoxy, ethoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl,phenoxycarbonyl, acetoxy, benzoyloxy, carbamoyl wherein the nitrogenatom may be independently mono or di-substituted by methyl or phenyl, orR_(c) is acetylamino, benzoylamino, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl or phenyl, orR_(c) is methoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy,phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino,methylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogenatom may be independently mono or di-substituted by methyl or phenyl, orR_(c) is chioro, fluoro, hydroxy, oxo, carboxy or cyano; R₂ and R₃together with the carbon the y are attached optionally form a ringselected from cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrofeiranyl, pytolidinyl, piperidinyl,piperazinyl, morpholinyl or tetrahydrothiophenyl; R₄ is hydrogen; R₅ isa bond, hydrogen, carbonyl, C1-5 alkyl, C1-5alkoxyC1-5alkyl,C1-5alkylaminoC1-5alkyl, C1-5alkylthioC1-5alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-5 alkoxy, phenoxy,naphthyloxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,tetrahydropyranyl, pyridinyl, and pyrimidinyl, heterocyclyloxy whereinthe heterocyclyl moiety is selected from the heterocycyl moieties hereindescribed in this paragraph, acetyl, benzoyl, acetyloxy, benzyloxy,methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzoyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by methyl, ethyl or phenyl, or R₅ is acetylamino,benzoylamino, phenylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by methyl, ethyl or phenyl, or R₅ ismethoxycarbonylamino, ethoxycarbonylamino, phenoxycarbonylamino,methylcarnamoyloxy, phenylcarbamoyloxy, phenylsulfonylamino,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl, or R₅is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R₅may befurther substituted or unsubstituted by one or more R_(e); R_(e) ismethyl ethyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl,phenyl, naphthyl, indanyl, piperidinyl, morpholinyl, indolyl, thienyl,pyridinyl, methoxy, ethoxy, acetyl, benzoyl, acetyloxy, phenoxy,benzyloxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl, or R_(e) is acetylamino, benzoylamino, methylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio methylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by methyl, ethyl or phenyl, or R_(e) ismethoxycarbonylamino, ethoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylarino,phenylsulfonylamino, methylaminosulfonyl, phenylamninosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl, ethyl or phenyl, or R_(e) is fluoro, chloro, hydroxy, oxo,carboxy or carboxamide, R_(e) may be further substituted orunsubstituted by one or more R_(f); and R_(f) is methyl, phenyl,tolylsulfonyl, phenoxy, benzyloxy, fluoro, chloro or oxo.
 15. Thecompound according to claim 14 wherein: R_(a) is methyl, cyclopropyl,phenyl, halogen, hydroxy, oxo, carboxy, cyano, nitro or carboxamide; R₃is a bond, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,n-pentyl, propenyl, i-butenyl, benzyl or naphthylmethyl wherein R₃ issubstituted or unsubstituted by one or more R_(c); R_(c) is methyl,ethyl, cyclohexyl, cyclopentyl, phenyl, furanyl, tetrahydropyranyl,thienyl, oxazolyl, thiazolyl, methoxy, phenoxy, acetyl, benzoyl,methoxycarbonyl, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by methyl or phenyl, or R_(c) isacetylamino, benzoylamino, methylthio, methoxycarbonylamino,methylcarbamoyloxy, methylsulfonylamino, methylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl, or R_(c) is fluoro or oxo; R₂ and R₃ together with the carbonthey are attached optionally form a ring selected from cyclopentyl,cyclohexyl, cycloheptyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrofuranyl, pyrrolidinyl or piperidinyl; and R₅ is methyl, ethyl,n-propyl, n-butyl, n-pentyl, 2-pentyl, 3-pentyl, phenethyl, phenpropyl,2,2-dimethylpropyl, t-butyl, i-propyl, i-butyl, cyclopropyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl, phenyl, benzyl, 2-methylbenzyl, 3-methylbenzyl,4-methylbenzyl, 2,6-dimethylbenzyl, 2,5-dimethylbenzyl,2,4-dimethylbenzyl, 2,3-dimethylbenzyl, 3,4-dimethylbenzyl,3,5-dimethylbenzyl, 2,4,6-trimethylbenzyl, 2-methoxybenzyl,3-methoxybenzyl, 4-methoxybenzyl, 2-phenoxybenzyl, 3-phenoxybenzyl,4-phenoxybenzyl, 2-benzyloxybenzyl,3-benzyloxybenzyl, 4-benzyloxybenzyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,6-difluorobenzyl,2,5-difluorobenzyl, 2,4-difluorobenzyl, 2,3-difluorobenzyl,3,4-difluorobenzyl, 3,5-difluorobenzyl, 2,4,6-triflurobenzyl,2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, naphthylmethyl, indanylmethyl, pyridinylmethyl,indolylmethyl, thienylmethyl, 5-methylthienylmethyl, piperidinyl,piperidinylcarbonyl, pyridinylcarbonyl, tetrahydropyranyl, pyrimidinyl,acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl,methylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxo or carboxy.16. The compound according to claim 15 wherein: R_(a) is methyl, phenyl,fluoro, chloro, hydroxy, oxo, carboxy or carboxamide; R₃ is a bond,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-pentyl, propenyl,i-butenyl or benzyl wherein R₃ is substituted or unsubstituted by one ormore R_(c); R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl,fuiranyl, tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, methoxy,phenoxy, acetyl, benzoyl, methoxycarbonyl, acetylamino, methylthio,methylsulfonylamino or fluoro; R₂ and R₃ together with the carbon theyare attached optionally form a ring selected from cyclopentyl,cyclohexyl, cycloheptyl, tetrahydropyranyl, tetrahydrothiopyranyl ortetrahydrofuranyl; and R₅ is methyl, ethyl, n-propyl, n-butyl,phenethyl, phenpropyl, t-butyl, i-propyl, i-butyl, cyclopropyl,cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, phenyl, benzyl,2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl 4-fluorobenzyl,3,5-difluorobenzyl, 4-trifluoromethylbenzyl, naphthylmethyl,pyridinylmethyl, indolylmethyl, thienylmethyl, acetyl, benzoyl,ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, phenylcarbamoyl,phenylsulfonylamino or fluoro.
 17. The compound according to claim 16wherein: R₁ is pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl; R₃ is n-propyl, i-butyl, propenyl, i-butenyl or2,2-dimethylpropyl; R₂ and R₃ together with the carbon they are attachedoptionally form a ring selected from cyclopentyl, cyclohexyl, orcycloheptyl; and R₅ is methyl, ethyl, n-propyl, phenethyl, t-butyl,i-propyl, i-butyl, cyclohexyl, cyclohexylmethyl, benzyl, 4-fluorobenzyl,naphthylmethyl, acetyl, benzoyl or benzyloxycarbonyl.
 18. A compoundselected from the group consisting of: Morpholine-4-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(1-benzyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amidehydrochloride; Morpholine-4-carboxylic acid{1-[4-cyano-1-(1-methyl-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;Morpholine-4-carboxylic acid[1-(4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid{1-[3-cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(4-cyano-1-isopropyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(1-phenethyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(1-n-propyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(1-benzyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-piperidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Pyrazine-2-carboxylic acid[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Pyrazine-2-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid{1-[3-cyano-1-(cyclohexyl-methyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-benzyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Pyrazine-2-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-methyl-ethyl)-pyrrolidin-3-ylcarbamoyl]-2cyclohexyl-ethyl}-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-methyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid{1-[3-cyano-1-(3-methyl-benzyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;Morpholine-4-carboxylic acid{1-[3-cyano-1-(2-methyl-pent-2-enyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;Morpholine-4-carboxylic acid{1-[3-cyano-1-(1H-indol-3-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;Pyrrolidine-1-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-isobutyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-isopropyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-isobutyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;Morpholine-4-carboxylic acid{1-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butyl}-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-phenethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopropylmethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-methyl-piperidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-azetidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-propyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid{1-[3-cyano-1-(trans-4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopentyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-isobutyl-piperidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopentyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid{1-[3-cyano-1-(trans-4-methyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butyl}-amide;Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-naphthalen-2-yl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-2-(4-chloro-phenyl)-ethyl]-amide;Morpholine-4-carboxylic acid{1-[3-cyano-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethyl}-amide;Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-but-3-enyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclopentylmethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;Pyrazine-2-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide;Morpholine-4-carboxylic acid[2-(4-chloro-phenyl)-1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-ethyl]-amide;Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-(3,4-dichloro-phenyl)-ethyl]-amide;Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-naphthalen-2-yl-ethyl]-amide;Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3-methyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(4-cyano-1,2-dimethyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amideand the pharmaceutically acceptable acceptable salts, esters, tautomers,individual isomers and mixtures of isomers thereof.
 19. The compoundaccording to claim 14 wherein the compound is selected from:Morpholine-4-carboxylic acid[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3-methyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(3-cyano-1-cyclohexylmethyl-pyrrolidin-3-ylcarbamoyl)-3-methyl-butyl]-amide;Morpholine-4-carboxylic acid[1-(1-benzyl-3-cyano-pyrrolidin-3-ylcarbamoyl)-3-methyl-but-3-enyl]-amideand the pharmaceutically acceptable acceptable salts, esters, tautomers,individual isomers and mixtures of isomers thereof.
 20. A compound offormula (Ia) or (Ib):

wherein: Het is piperidinyl, pyrrolidinyl or azetidinyl each beingsubstituted or unsubstituted with one or more R₅; R₁ is a pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, pyrazinyl or piperazinyl;wherein R₁ is substituted or unsubstituted by one or more R₅; R_(a) is abond, C1-10 alkyl, C3-8 cycloalkyl, aryl, tetrahydronaphthyl, indenyl,indanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, C1-10 alkoxy, C1-10alkanoyl, C1-10alkanoyloxy, aryloxy,benzyloxy, C1-10 alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(a) is C1-10 alkanoylamino, aroylamino, C1-10alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxideor sulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(a) is C1-10 alkoxycarbonylamino,aryloxycarbonylamino, C1-10 alkylcarbamoyloxy, arylcarbamoyloxy, C1-10alkylsulfonylamino, arylsulfonylamino, C1-10 alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(a) is halogen, hydroxy, oxo, carboxy, cyano,nitro, carboxamide, amidino or guanidino, R_(a) may be furthersubstituted or unsubstituted by one or more R_(b); with the proviso thatR_(1 and R) _(a) simultaneously cannot be a bond; R_(b) is a C1-6saturated or unsaturated branched or unbranched carbon chain optionallypartially or fully halogenated wherein one or more carbon atoms areoptionally replaced by O, N, S(O), S(O)₂ or S and wherein said chain isoptionally independently substituted with 1-2 oxo groups, —NH₂, or oneor more C1-4 alkyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl; or R_(b) is C3-6 cycloalkyl, aryl, aryloxy, benzyloxy,halogen, hydroxy, oxo, carboxy, cyano, nitro, mono-C1-5alkylamino,di-C1-5alkylamino, carboxamide, amidino or guanidino; R₂ is hydrogen orC1-3 alkyl; R₃ is a bond, hydrogen, C1-10 alkyl, C2-10alkylene, C3-8cycloalkyl, arylC1-5alkyl or aryl wherein R₃ is substituted orunsubstituted by one or more R_(c); R_(c) is C1-10 alkyl, C3-8cycloalkyl, aryl, indanyl, indenyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl,bicyclo[1.1.1]pentanyl, cubanyl, 1,2,3,4-tetrahydronaphthyl,decahydronaphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, tetrahydrofuranyl,pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, dihydrobenzofuranyl,octohydrobenzofuranyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, tetrahydroquinolinyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-10 alkoxy, aryloxy, C1-10 alkanoyl, aroyl, C1-10 alkoxycarbonyl,aryloxycarbonyl, C1-10 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, or R_(c) isC1-10 alkanoylamino, aroylamino, C1-10 alkylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, arylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-10 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R_(c) is C1-10alkoxycarbonylamino, aryloxycarbonylamino, C1-10 alkylcarbamoyloxy,arylcarbamoyloxy, C1-10 alkylsulfonylamino, arylsulfonylamino, C1-10alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-10 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R_(c) is halogen,hydroxy, oxo, carboxy, cyano, nitro, amidino or guanidino, R_(c) may befurther substituted or unsubstituted by one or more R_(d); R_(d) is C1-5alkyl, C3-6 cycloalkyl, aryl, arylC1-5alkyl, C1-5 alkoxy, aryloxy,arylC1-5alkoxy, aroyl, amino, halogen, hydroxy, oxo, carboxy, cyano,nitro, amidino or guanidino; R₂ and R₃ together with the carbon they areattached optionally form a nonaromatic 5-7 membered cycloalkyl orheterocyclic ring; each R₄ is independently hydrogen, hydroxy or C1-3alkyl; R₅ is a bond, hydrogen, carbonyl, C1-10 alkyl,C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl,C1-10alkylthioC1-10alkyl wherein the sulfur atom may be oxidized to asulfoxide or sulfone, C1-10 alkoxy, aryloxy, C3-8 cycloalkyl, aryl,benzyl, tetrahydronaphthyl, indenyl, indanyl,C3-7cycloalkylsulfonylC1-5alkyl, arylsulfonylC1-5alkyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, thiopyranyl,tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridizinyl, tetrazolyl, triazolyl, pyrazolyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,quinazolinyl, tetrahydroquinazolinyl, benzoxazolyl and quinoxalinyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from theheterocycyl moieties herein described in this paragraph, C1-10alkanoyl,aroyl, C1-10alkanoyloxy, benzyloxy, C1-10alkoxycarbonyl,arylC1-5alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl, or R₅ is C1-10alkanoylamino, aroylamino, C1-10 alkylthio wherein the sulfur atom maybe oxidized to a sulfoxide or sulfone, arylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-10 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R₅ is C1-10alkoxycarbonylamino, aryloxycarbonylamino, C1-10 alkylcarbamoyloxy,arylcarbamoyloxy, C1-10 alkylsulfonylamino, arylsulfonylamino, C1-10alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-10 alkyl, aryl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl, or R₅ is halogen, hydroxy,oxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino, R₅may be further substituted or unsubstituted by one or more R_(e); R_(e)is C1-10 alkyl, C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl,C1-10alkylthioC1-10alkyl wherein the sulfur atom may be oxidized to asulfoxide or sulfone, C1-10 alkoxy, C3-8 cycloalkyl, aryl,tetrahydronaphthyl, indenyl, indanyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, thiopyranyl,tetrahydrothiopyranyl, pyranyl, tetrahydropyranyl, tetrahydrofuranyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-10alkanoyl, aroyl, C1-10alkanoyloxy, aryloxy, benzyloxy, C1-10alkoxycarbonyl, arylC1-3alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(e) is C1-10 alkanoylamino, aroylamino, C1-10alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxideor sulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(e) is C1-10 alkoxycarbonylamino,aryloxycarbonylamino, C1-10 alkylcarbamoyloxy, arylcarbamoyloxy, C1-10alkylsulfonylamino, arylsulfonylamino, C1-10 alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl, or R_(e) is halogen, hydroxy, oxo, carboxy, cyano,nitro, carboxamide, amidino or guanidino, R_(e) may be furthersubstituted or unsubstituted by one or more R_(f); R_(f) is C1-5 alkyl,C3-6 cycloalkyl, tolylsulfonyl, C1-5 alkoxy, aryl, aryloxy, benzyloxy,halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino orguanidino; R₆ is hydrogen, hydroxy, nitrile or a C1-6 saturated orunsaturated branched or unbranched carbon chain optionally partially orfully halogenated wherein one or more C atoms are optionally replaced byO, NH, S(O), S(O)₂ or S and wherein said chain is optionallyindependently substituted with 1-2 oxo groups, —NH₂, one or more C₁₋₄alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,benzoxazolyl or quinoxalinyl; each R₈ is independently: C1-5 alkyl chainoptionally interrupted by one or two N, O or S(O)_(m) and substituted orunsubstituted by 1-2 oxo, amino, hydroxy, halogen, C1-4alkyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, pyranyl, thiopyranyl, fuiranyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl or quinoxalinyl,aryl, aryloxy, aroyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyridinyl,pyrimidinyl, C1-5 alkanoyl, C1-5 alkoxycarbonyl, aryloxycarbonyl,benzyloxycarbonyl, C1-5 alkanoylamino, aroylamino, C1-5 alkylthio,arylthio C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, C3-6 cycloalkyl and benzyloxyeach of the aforementioned are optionally halogenated, halogen, hydroxy,oxo, carboxy, nitrile, nitro or NH₂C(O)—; m is 0, 1 or 2; X is O, andpharmaceutically acceptable acceptable salts, esters, tautomers,individual isomers and mixtures of isomers thereof.
 21. The compoundaccording to claim 20 wherein: R₁ is pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, pyrazinyl or piperazinyl; wherein R₁ issubstituted or unsubstituted by one or more R_(a); R_(a) is a bond, C1-3alkyl, cyclopropyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, thienyl, imidazolyl, C1-3alkoxy, C1-3alkanoyl, C1-3alkanoyloxy, aryloxy, benzyloxy, C1-3alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl orpiperazinyl, or R_(a) is C1-3 alkanoylamino, aroylamino, C1-3 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl, or R_(a) is C1-3 alkoxycarbonylamino,aryloxycarbonylamino, C1-3 alkylcarbamoyloxy, arylcarbamoyloxy, C1-3alkylsulfonylamino, arylsulfonylamino, C1-3 alkylaminosulfonyl,arylaminosulfonyl, amino wherein the nitrogen atom may be independentlymono or di-substituted by C1-3 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl or piperazinyl, or R_(a) is halogen,hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino,R_(a) may be further substituted or unsubstituted by one or more R_(b);R_(b) is methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, i-propoxy, phenoxy,benzyloxy, fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy, cyano,nitro or carboxamide; R₂ is hydrogen; R₃ is a bond, C1-3 alkyl,C2-4alkylene, C5-6 cycloalkyl, benzyl or naphthylmethyl wherein R₃ issubstituted or unsubstituted by one or more R_(c); R_(c) is C1-3 alkyl,C5-6 cycloalkyl, phenyl, naphthyl, indanyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl,bicyclo[1.1.1]pentanyl, cubanyl, 1,2,3,4-tetrahydronaphthyl, furanyl,tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyrimidinyl, indolyl, benzofuranyl, benzothienyl, benzthiazolyl, C1-3alkoxy, phenoxy, naphthyloxy, C1-2 alkanoyl, benzoyl, C1-2alkoxycarbonyl, phenoxycarbonyl, C1-2alkanoyloxy, benzoyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl or aryl, or R_(c) is C1-2 alkanoylamino, benzoylamino, C1-2alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, phenylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by C1-3 alkyl or aryl, or R_(c) is C1-2alkoxycarbonylamino, phenoxycarbonylamino, C1-2 alkylcarbamoyloxy,arylcarbamoyloxy, C1-2 alkylsulfonylamino, phenylsulfonylamino,C1-2alkylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogenatom may be independently mono or di-substituted by C1-3 alkyl orphenyl, or R_(c) is halogen, hydroxy, oxo, carboxy or cyano, R_(c) maybe further substituted or unsubstituted by one or more R_(d); R_(d) ismethyl, cyclopropyl, cyclohexyl, phenyl, benzyl, methoxy, phenoxy,benzyloxy, benzoyl, fluoro, chloro, oxo or cyano; R₄ is hydrogen; R₅ isa bond, hydrogen, carbonyl, C1-5 alkyl, C1-5alkoxyC1-5alkyl,C1-5alkylaminoC1-5alkyl, C1-5alkylthioC1-5alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-5 alkoxy, phenoxy, C3-6cycloalkyl, phenyl, naphthyl, benzyl, indanyl, heterocyclyl selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl and benzthiazolyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from theheterocycyl moieties herein described in this paragraph, C1-3alkanoyl,benzoyl, naphthoyl, C1-3alkanoyloxy, benzyloxy, C1-3 alkoxycarbonyl,benzyloxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl, or R₅ is C1-3alkanoylamino, aroylamino, C1-3 alkylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, phenylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-3 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzofuranyl,benzothienyl, benzimidazolyl or benzthiazolyl, or R₅ is C1-3alkoxycarbonylamino, phenoxycarbonylamino, C1-3 alkylcarbamoyloxy,phenylcarbamoyloxy, C1-3 alkylsulfonylamino, phenylsulfonylamino, C1-3alkylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-3 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolylor benzthiazolyl, or R₅ is halogen, hydroxy, oxo, carboxy, cyano orcarboxamide, R₅ may be further substituted or unsubstituted by one ormore R_(e); R_(e) is C1-3 alkyl, C1-3 alkoxy, C3-7 cycloalkyl, phenyl,naphthyl, indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,C1-3 alkanoyl, aroyl, C1-3 alkanoyloxy, phenoxy, benzyloxy, C1-3alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl orbenzthiazolyl, or R_(e) is C1-3 alkanoylamino, benzoylamino, C1-3alkylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, phenylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by C1-3 alkyl, phenyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl, or R_(e) isC1-3 alkoxycarbonylamino, phenoxycarbonylamino, C1-3 alkylcarbamoyloxy,phenylcarbamoyloxy, C1-3 alkylsulfonylamino, phenylsulfonylamino, C1-3alkylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-3 alkyl, phenyl,naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl orbenzthiazolyl, or R_(e) is halogen, hydroxy, oxo, carboxy, cyano orcarboxamide, R_(e) may be further substituted or unsubstituted by one ormore R_(f); R_(f) is methyl, phenyl, tolylsulfonyl, methoxy, phenoxy,benzyloxy, fluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide;and R₆ is hydroxy, nitrile or a C1-5 saturated or unsaturated branchedor unbranched carbon chain optionally partially or fully halogenatedwherein one or more C atoms are optionally replaced by O, NH, or S(O)₂and wherein said chain is optionally independently substituted with 1-2oxo groups, —NH₂, one or more C1-4 alkyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl,thiopyranyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl, benzoxazolyl or quinoxalinyl.
 22. Thecompound according to claim 21 wherein: R_(a) is a bond, methyl, ethyl,cyclopropyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, thienyl, imidazolyl, methoxy, acetyl,acetoxy, phenoxy, benzyloxy, methoxycarbonyl, phenoxycarbonyl,benzoyloxy, carbamoyl wherein the nitrogen atom may be independentlymono or di-substituted by methyl, ethyl or phenyl, or R_(a) isacetylamino, benzoylamino, methylthio, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl orphenyl, or R_(a) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl, or R_(a) is fluoro, chloro, bromo, iodo, hydroxy, oxo,carboxy, cyano, nitro or carboxamide, R_(a) may be further substitutedor unsubstituted by one or more R_(b); R_(b) is methyl, cyclopropyl,phenyl, methoxy, phenoxy, benzyloxy, fluoro, chloro, hydroxy, oxo,carboxy or carboxamide; R₃ is a bond, C1-3 alkyl, C2-4alkylene, C5-6cycloalkyl, benzyl or naphthylmethyl wherein R₃ is substituted orunsubstituted by one or more R_(c); R_(c) is methyl, ethyl, n-propyl,i-propyl, C5-6 cycloalkyl, indanyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl,bicyclo[1.1.1]pentanyl, cubanyl, 1,2,3,4-tetrahydronaphthyl, thienyl,oxazolyl, thiazolyl, indolyl, benzofuranyl, benzothienyl, benzthiazolyl,methoxy, ethoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl,phenoxycarbonyl, acetoxy, benzoyloxy, carbamoyl wherein the nitrogenatom may be independently mono or di-substituted by methyl, ethyl oraryl, or R_(c) is acetylamino, benzoylamino, methylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl or aryl, or R_(c) is methoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl, orR_(c) is fluoro, chloro or oxo, R_(c) may be further substituted orunsubstituted by one or more R_(d); R_(d) is methyl, cyclopropyl,phenyl, methoxy, fluoro, chloro or oxo; R₅ is a bond, hydrogen,carbonyl, C1-4 alkyl, C1-4alkoxyC1-4alkyl , C1-4alkylaminoC1-4alkyl,C1-4alkylthioC1-4alkyl wherein the sulfur atom may be oxidized to asulfoxide or sulfone, C1-4 alkoxy, phenoxy, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, naphthyl, benzyl, indanyl, heterocyclyl selectedfrom pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, benzimidazolyl and benzthiazolyl, heterocyclyloxy whereinthe heterocyclyl moiety is selected from the heterocycyl moieties hereindescribed in this paragraph, C1-2alkanoyl, benzoyl, naphthoyl,C1-2alkanoyloxy, benzyloxy, C1-2 alkoxycarbonyl, benzyloxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl, or R₅ is C1-2alkanoylamino, benzoylamino, C1-2 alkylthio wherein the sulfur atom maybe oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl orbenzthiazolyl, or R_(5 is C)1-2 alkoxycarbonylamino,phenoxycarbonylamino, C1-2 alkylcarbamoyloxy, phenylcarbamoyloxy, C1-2alkylsulfonylamino, phenylsulfonylamino, C1-2 alkylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl, or R₅ is fluoro,chloro, bromo, hydroxy, oxo, carboxy or carboxamide, R₅ may be furthersubstituted or unsubstituted by one or more R_(e); R_(e) is C1-3 alkyl,C1-2 alkoxy, C3-6 cycloalkyl, phenyl, naphthyl, indanyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, indolyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, C1-2 alkanoyl, aroyl,C1-2alkanoyloxy, phenoxy, benzyloxy, C1-2 alkoxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl, or R_(e) is C1-2alkanoylamino, benzoylamino, C1-2 alkylthio wherein the sulfur atom maybe oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl, or R_(e) is C1-2alkoxycarbonylamino, phenoxycarbonylamino, C1-2 alkylcarbamoyloxy,phenylcarbamoyloxy, C1-2 alkylsulfonylamino, phenylsulfonylamino, C1-2alkylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogen atommay be independently mono or di-substituted by C1-2 alkyl, phenyl,naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl, or R_(e) is fluoro,chloro, bromo, hydroxy, oxo, carboxy or carboxamide, R_(e) may befurther substituted or unsubstituted by one or more R_(f); R_(f) ismethyl, phenyl, tolylsulfonyl, methoxy, phenoxy, benzyloxy, fluoro,chloro, hydroxy, oxo, carboxy or carboxamide; and R₆ is nitrile or aC1-5 saturated or unsaturated branched or unbranched carbon chainoptionally partially or fully halogenated wherein one or more C atomsare optionally replaced by O, NH, or S(O)₂ and wherein said chain isoptionally independently substituted with oxo, —NH₂, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, pyridinyl, pyrimidinyl orpyrazinyl.
 23. The compound according to claim 22 wherein: Het ispiperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl, azetidin-3-yl, eachring being substituted or unsubstituted with one or more R₅; R_(a) ismethyl, phenyl, thienyl, methoxy, acetyl, acetoxy, phenoxy, benzyloxy,methoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by methyl or phenyl, or R_(a) isacetylamino, methylthio, phenylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atommay be independently substituted by methyl or phenyl, or R_(a) ismethoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, amino wherein the nitrogenatom may be independently mono or di-substituted by methyl or phenyl, orR_(a) is fluoro, chloro, hydroxy, oxo, carboxy, cyano or carboxamide; R₃is a bond, methyl, ethyl, n-propyl, propenyl, butenyl, i-butenyl,cyclohexyl, benzyl or naphthylmethyl wherein R₃ is substituted orunsubstituted by one or more R_(c); R_(e) is methyl, ethyl, n-propyl,i-propyl, cyclohexyl, cyclopentyl, indanyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl,bicyclo[1.1.1]pentanyl, cubanyl, 1,2,3,4-tetrahydronaphthyl, methoxy,phenoxy, acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, acetoxy,benzoyloxy, methylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, phenylthio wherein the sulfur atom may be oxidizedto a sulfoxide or sulfone, fluoro, chloro or oxo; wherein theconfiguration at the asymmetric carbon atom defined by R₂ and R₃ whenthey are different is the L enantiomer; and R₅ is a bond, hydrogen,carbonyl, C1-4 alkyl, C1-2alkoxyC1-2alkyl, C1-2alkylaminoC1-2alkyl,C1-2alkylthioC1-2alkyl wherein the sulfur atom may be oxidized to asulfoxide or sulfone, C1-2 alkoxy, phenoxy, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, benzyl, heterocyclyl selected from pyrrolidinyl,piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl, and pyrimidinyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from theheterocycyl moieties herein described in this paragraph, acetyl,benzoyl, acetyloxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl,benzyloxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom maybe independently mono or di-substituted by methyl, ethyl or phenyl, orR₅ is acetylamino, benzoylamino, methylthio wherein the sulfur atom maybe oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl orphenyl, or R₅ is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl, or R₅is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R₅ may befurther substituted or unsubstituted by one or more R_(e); R_(e) ismethyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl,naphthyl, indanyl, piperidinyl, morpholinyl, indolyl, thienyl,pyridinyl, acetyl, benzoyl, acetyloxy, phenoxy, benzyloxy,methoxycarbonyl, ethoxycarbonyl, carbamoyl wherein the nitrogen atom maybe independently mono or di-substituted by methyl, ethyl or phenyl, orR_(e) is acetylamino, benzoylamino, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl orphenyl, or R_(e) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl, orR_(e) is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R_(e) maybe further substituted or unsubstituted by one or more R_(f); R_(f) ismethyl, phenyl, tolylsulfonyl, phenoxy, benzyloxy, fluoro, chloro oroxo; and R₆ is nitrile or a C1-5 saturated or unsaturated branched orunbranched carbon chain optionally partially or fully halogenatedwherein one or more C atoms are optionally replaced by O, NH, or S(O)₂and wherein said chain is optionally independently substituted with oxo,—NH₂, morpholinyl or piperazinyl.
 24. The compound according to claim 23wherein: R₁ is piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl orpyrazinyl; R₃ is ethyl, n-propyl,propenyl, butenyl, i-butenyl, benzyl ornaphthylmethyl wherein R₃ is substituted or unsubstituted by one or moreR_(c); R_(c) is methyl, cyclohexyl, cyclopentyl, indanyl,1,2,3,4-tetrahydronaphthyl, methoxy, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, fluoro or chloro; R₅ is abond, carbonyl, methyl, ethyl, n-propyl, n-butyl, t-butyl, i-propyl,i-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl,piperidinyl, tetrahydropyranyl, pyrimidinyl, acetyl, benzoyl,ethoxycarbonyl, benzyloxycarbonyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxo or carboxy,R₅ may be further substituted or unsubstituted by one or more R_(e);R_(e) is methyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl,indanyl, thienyl, 5-methylthienyl, methoxy, phenoxy, benzyloxy,piperidinyl, pyridinyl, indolyl, 1-(tolyl-sulfonyl)-indolyl, carbamoylwherein the nitrogen atom may be independently mono or di-substituted bymethyl, phenyl or benzyl, or R_(e) is hydroxy, fluoro, chloro, oxo,dimethylamino or trifluoromethyl; and R₆ is acetyl,C1-3alkylaminocarbonyl or C1-3alkoxycarbonyl.
 25. The compound accordingto claim 24 wherein: Het is piperidin-4-yl or pyrrolidin-3-yl; R₁ ismorpholin-4-yl; R₅ is methyl, propyl, n-pentyl or cyclohexyl and R₆ isacetyl, ethylaminocarbonyl or ethoxycarbonyl.
 26. The compound accordingto claim 20 wherein: R₁ is pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl or pyrazinyl; wherein R₁ is substituted orunsubstituted by one or more R_(a); R_(a) is methyl, ethyl, propyl,i-propyl, cyclopropyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, thienyl, imidazolyl, methoxy,ethoxy, acetyl, acetoxy, phenoxy, naphthyloxy, benzyloxy,methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, naphthyloxycarbonyl,benzoyloxy, carbamoyl wherein the nitrogen atom may be independentlymono or di-substituted by methyl, ethyl, phenyl, naphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, or R_(a) isacetylamino, benzoylamino, methylthio wherein the sulfur atom may beoxidized to a sulfoxide or sulfone, ethylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl, phenyl,naphthyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl orpiperazinyl, or R_(a) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, C1-2 alkylcarbamoyloxy, phenylcarbamoyloxy,naphthylcarbamoyloxy, C1-2 alkylsulfonylamino, phenylsulfonylamino,naphthylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl,naphthylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl, phenyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino, R_(a) may be further substituted or unsubstitutedby one or more R_(b); R_(b) is methyl, ethyl, cyclopropyl, cyclohexyl,phenyl, methoxy, ethoxy, phenoxy, benzyloxy, fluoro, chloro, bromo,hydroxy, oxo, carboxy, cyano, nitro or carboxamide; R₂ is hydrogen ormethyl; R₃ is a bond, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, n-pentyl, propenyl, i-butenyl, cyclohexyl, benzyl ornaphthylmethyl wherein R₃ is substituted or unsubstituted by one or moreR_(c); R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl,naphthyl, bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,furanyl, tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyrimidinyl, methoxy, ethoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl,phenoxycarbonyl, acetoxy, benzoyloxy, carbamoyl wherein the nitrogenatom may be independently mono or di-substituted by methyl or phenyl, orR_(c) is acetylamino, benzoylamino, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl or phenyl, orR_(c) is methoxycarbonylamino, phenoxycarbonylamino, methylcarbamoyloxy,phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino,methylaminosulfonyl, phenylaminosulfonyl, amino wherein the nitrogenatom may be independently mono or di-substituted by methyl or phenyl, orR_(c) is chloro, fluoro, hydroxy, oxo, carboxy or cyano; R₂ and R₃together with the carbon they are attached optionally form a ringselected from cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl or tetrahydrothiophenyl; R₄ is hydrogen; R₅ isa bond, hydrogen, carbonyl, C1-5 alkyl, C1-5alkoxyC1-5alkyl,C1-5alkylaminoC1-5alkyl, C1-5alkylthioC1-5alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-5 alkoxy, phenoxy,naphthyloxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,tetrahydropyranyl, pyridinyl, and pyrimidinyl, heterocyclyloxy whereinthe heterocyclyl moiety is selected from the heterocycyl moieties hereindescribed in this paragraph, acetyl, benzoyl, acetyloxy, benzyloxy,methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzoyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by methyl, ethyl or phenyl, or R₅ is acetylamino,benzoylamino, phenylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by methyl, ethyl or phenyl, or R₅ ismethoxycarbonylamino, ethoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, phenylsulfonylamino,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl, or R₅is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R₅ may befurther substituted or unsubstituted by one or more R_(e); R_(e) ismethyl ethyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl,phenyl, naphthyl, indanyl, piperidinyl, morpholinyl, indolyl, thienyl,pyridinyl, methoxy, ethoxy, acetyl, benzoyl, acetyloxy, phenoxy,benzyloxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl, or R_(e) is acetylamino, benzoylamino, methylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio methylthio wherein the sulfur atom may be oxidized to asulfoxide or sulfone, ureido wherein either nitrogen atom may beindependently substituted by methyl, ethyl or phenyl, or R_(e) ismethoxycarbonylamino, ethoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl, ethyl or phenyl, or R_(e) is fluoro, chloro, hydroxy, oxo,carboxy or carboxamide, R_(e) may be further substituted orunsubstituted by one or more R_(f); and R_(f) is methyl, phenyl,tolylsulfonyl, phenoxy, benzyloxy, fluoro, chloro or oxo.
 27. Thecompound according to claim 26 wherein R_(a) is methyl, cyclopropyl,phenyl, halogen, hydroxy, oxo, carboxy, cyano, nitro or carboxamide; R₃is a bond, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,n-pentyl, propenyl, i-butenyl, benzyl or naphthylmethyl wherein R₃ issubstituted or unsubstituted by one or more R_(c); R_(c) is methyl,ethyl, cyclohexyl, cyclopentyl, phenyl, furanyl, tetrahydropyranyl,thienyl, oxazolyl, thiazolyl, methoxy, phenoxy, acetyl, benzoyl,methoxycarbonyl, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by methyl or phenyl, or R_(c) isacetylamino, benzoylamino, methylthio, methoxycarbonylamino,methylcarbamoyloxy, methylsulfonylamino, methylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl, or R_(c) is fluoro or oxo; R₂ and R₃ together with the carbonthey are attached optionally form a ring selected from cyclopentyl,cyclohexyl, cycloheptyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrofuranyl, pyrrolidinyl or piperidinyl; and R₅ is methyl, ethyl,n-propyl, n-butyl, n-pentyl, 2-pentyl, 3-pentyl, phenethyl, phenpropyl,2,2-dimethylpropyl, t-butyl, i-propyl, i-butyl, cyclopropyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl, phenyl, benzyl, 2-methylbenzyl, 3-methylbenzyl,4-methylbenzyl, 2,6-dimethylbenzyl, 2,5-dimethylbenzyl,2,4-dimethylbenzyl, 2,3-dimethylbenzyl, 3,4-dimethylbenzyl,3,5-dimethylbenzyl, 2,4,6-trimethylbenzyl, 2-methoxybenzyl,3-methoxybenzyl, 4-methoxybenzyl, 2-phenoxybenzyl, 3-phenoxybenzyl,4-phenoxybenzyl, 2-benzyloxybenzyl,3-benzyloxybenzyl, 4-benzyloxybenzyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,6-difluorobenzyl,2,5-difluorobenzyl, 2,4-difluorobenzyl, 2,3-difluorobenzyl,3,4-difluorobenzyl, 3,5-difluorobenzyl, 2,4,6-triflurobenzyl,2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, naphthylmethyl, indanylmethyl, pyridinylmethyl,indolylmethyl, thienylmethyl, 5-methylthienylmethyl, piperidinyl,piperidinylcarbonyl, pyridinylcarbonyl, tetrahydropyranyl, pyrimidinyl,acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl,methylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxo or carboxy.28. The compound according to claim 27 wherein: R_(a) is methyl, phenyl,fluoro, chloro, hydroxy, oxo, carboxy or carboxamide; R₃ is a bond,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-pentyl, propenyl,i-butenyl or benzyl wherein R₃ is substituted or unsubstituted by one ormore R_(c); R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl,furanyl, tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, methoxy,phenoxy, acetyl, benzoyl, methoxycarbonyl, acetylamino, methylthio,methylsulfonylamino or fluoro; R₂ and R₃ together with the carbon theyare attached optionally form a ring selected from cyclopentyl,cyclohexyl, cycloheptyl, tetrahydropyranyl, tetrahydrothiopyranyl ortetrahydrofuranyl; and R₅ is methyl, ethyl, n-propyl, n-butyl,phenethyl, phenpropyl, t-butyl, i-propyl, i-butyl, cyclopropyl,cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, phenyl, benzyl,2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl 4-fluorobenzyl,3,5-difluorobenzyl, 4-trifluoromethylbenzyl, naphthylmethyl,pyridinylmethyl, indolylmethyl, thienylmethyl, acetyl, benzoyl,ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, phenylcarbamoyl,phenylsulfonylamino or fluoro.
 29. The compound according to claim 28wherein: Het is pyrrolidinyl or piperidinyl; R₁ is pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl; R₃ isn-propyl, i-butyl, propenyl, i-butenyl or 2,2-dimethylpropyl; R₂ and R₃together with the carbon they are attached optionally form a ringselected from cyclopentyl, cyclohexyl, or cycloheptyl; and R₅ is methyl,ethyl, n-propyl, phenethyl, t-butyl, i-propyl, i-butyl, cyclohexyl,cyclohexylmethyl, benzyl, 4-fluorobenzyl, naphthylmethyl, acetyl,benzoyl or benzyloxycarbonyl.
 30. A compound selected from:{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester;N-(4-Cyano-methyl-piperidin-4-yl)-3-cyclohexyl-2-(3-oxo-3H-isoindol-1-ylamino)-propionamide;4,4-Dimethyl-2-(3-oxo-3H-isoindol-1-ylamino)-pentanoicacid-(4-cyano-1-propyl-piperidin-4-yl)-amide;N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-piperidin-1-yl-methyl}-carbamicacid ethyl ester;′2-[(Acetylimino-phenyl-methyl)-amino]-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide;′{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylen}-carbamicacid ethyl ester;′2-[(Acetylimino-phenyl-methyl)-amino]-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide;′({1-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester;′N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-phenyl-methyl)-amino]-propionamide;′N-[4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide;′N-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide;N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide;N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide;N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide;′2-(1,1-Dioxo-1H-λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide and the pharmaceuticallyacceptable acceptable salts, esters, tautomers, individual isomers andmixtures of isomers thereof.
 31. A pharmaceutical composition comprisinga pharmaceutically effective amount of a compound according to claims 1,6, 14 or
 20. 32. A method of modulating an autoimmune disease, saidmethod comprising administering to a patient in need of such treatment apharmaceutically effective amount of a compound according to claim 1, 6or
 20. 33. The method according to claim 32 wherein the autoimmunedisease is rheumatoid arthritis, systemic lupus erythematosus, Crohn'sdisease, ulcerative colitis, multiple sclerosis, Guillain-Barresyndrome, psoriasis, Grave's disease, myasthenia gravis, scleroderma,glomerulonephritis, atopic dermatitis, asthma or insulin-dependentdiabetes mellitus.
 34. A method of treating Alzheimer's diseasecomprising administering to a patient in need of such treatment apharmaceutically effective amount of a compound according to claim 1, 6or
 20. 35. A method of treating atherosclerosis comprising administeringto a patient in need of such treatment a pharmaceutically effectiveamount of a compound according to claim 1, 6 or
 20. 36. A method oftreating osteoporosis comprising administering to a patient in need ofsuch treatment a pharmaceutically effective amount of a compoundaccording to claims 6, 14 or
 26. 37. A method of making a compound ofthe formula (I)

wherein Y, X, R₁, R₂, R₃, R₄, Het and R₅ are as defined in claim 1; saidmethod comprising: a) reacting an amino acid ester (IV), wherein R′ is aprotecting group, under suitable reaction conditions with a R₁C(O)Lwherein L is a leaving group selected from Cl and OH:

b) removing the protecting group R′ from the compound produced in stepa) to produce the corresponding carboxylic acid; c) reacting the productof step b) under coupling conditions consisting of EDC and HOBT in asolvent selected from DMF and methylene chloride, with an amino nitrilebearing “Het-R₅” shown below to produce a compound of the formula (I):